Parkinson Disease Information

The Parkinson's-Reversing Breakthrough

The Parkinson's Breakthrough Program entails the most effective and natural strategies people can use to heal the root cause of Parkinson's Disease. It is a digital manual aimed at showing the users the most effective method for overcoming Parkinson's without high-priced prescription drugs riddled with harmful side effects.The program was not created to be a quick fix. In fact, like different programs, it is tasking. Yet, you will not have to spend a lot of time dealing with it. The system requires your full attention, perseverance, and discipline. For the period of its usage, you will have the opportunity to use to eat some food ingredients that will detoxify you.The methods employed in this book are natural ones that have been proven by many specialists. The users will be privy to what to do and what not to do to treat the underlying root cause of their Parkinson's and the way they can reverse the symptoms naturally and effectively. The system comes with bonus E-books- Lessons from The Miracle Doctors, Mind Control in the USA', and 10 Deadly Health Myths of The 21st Century. The book is in a digital format (PDF) and has been created at a very affordable price. More here...

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Aaad Activity in pd Models

Clues supporting the idea that AAAD can be subjected to pharmacological manipulation in PD. For example, therapeutic infusion of L-DOPA or apomorphine caused a small decrease in L- nC DOPA influx in the striatum with early but not advanced PD 107,108 , and decreases in putamen AAAD activity following a 2 year treatment with L-DOPA, -20.3 , or a D2 agonist, -13.4 have been reported 109 .

Project Title Mitochondrial Metabolites To Treat Parkinsons

Summary Mitochondrial decay due to oxidation is an important contributor to Parkinson's disease (PD) and other neurodegenerative diseases of aging. We have previously shown that mitochondrial decay in old rats can be ameliorated by feeding them the normal mitochondrial metabolites R-alpha-lipoic acid (LA) and acetyl-L-carnitine (ALCAR), which inhibited oxidative damage and restored much of the mitochondrial structure and function in old animals. There is evidence that some mitochondrial metabolites may protect against PD. For example, coenzyme Q10 (CoQ) has been shown to protect against PD in clinical trials in humans and ALCAR has been shown to protect against (MPTP)-induced

Project Title Oxidative Stress In Novel Models Of Parkinsons Disease

Summary (Verbatim from the Applicant's Abstract) The goal of this research is to understand the role of mitochondrial dysfunction and oxidative stress in Parkinson's disease (PD). These experiments will utilize both a novel in viovo model of PD as well a a cell culture model to elucidate the mechanisms by which complex I inhibition and oxidative damage result in neuronal cell death. Chronic, systemic rotenone treatment to rats will be used as a model of complex I dysfunction and selective nigrostriatal dopaminergic neurodegeneration seen in PD. Specifically, levels of aoxidative stress will be determined biochemically using an oxyblot technique. Regional distribution of oxidative damage will be studied using immunocytochemical protocols. Additionally, a c ell culture model in which cells are treated chronically with sublethal doses of rotenone will be used. In this system, we will use fluorescent techniques to determine whether chronic complex I dysfunction increases the...

Dopaminemediated Oxidative Stress and Neuroinflammation in pd

PD is a progressive neurodegenerative disorder of nigrostriatal DA-ergic system. It is characterized by the loss of DA-ergic neurons in the substantia nigra pars compacta (SNpC) that control muscle movement 72 , 50-70 loss of striatal dopamine, presence of Lewy bodies (intracytoplasmic protein aggregates mainly composed of a-synuclein in the midbrain 73 , and mitochondrial complex I deficiency in the SNpc 74-76 . Although, molecular mechanism associated with the pathogenesis of PD is not fully understood. However, involvement of oxidative stress, inflammation, excitotoxicity, cytokine activation, mitochondrial dysfunction, and ubiquitin-proteasomal impairment has been suggested in PD 77-81 . In this review, I will emphasize the involvement of oxidative stress and neuroinflammation, because these processes have recently taken center stage for neurodegeneration in PD (Figure 6). Figure 6. Possible ROS RNS-mediated oxidative stress pathways implicating neurodegeneration of DA-ergic...

In The Substantia Nigra Pars Compacta

There is little doubt that neurons (or any other cell types for that matter) would die if subjected to the postulated harsh oxidative insults likely to be encountered in certain acute neurological disorders such as ischemia and stroke. In PD, however, there is no evidence that SNpc DA neurons face such a severe insult. On the other hand, because PD is a chronic disorder, a much milder oxidative stress may cause a buildup of ROS-mediated damage over several years, leading to progressive cellular dysfunction which ultimately commits the neuron to die.

Nitric Oxide Overproduction and Oxidative Stress in Human Idiopathic Parkinsons Disease

Neurodegenerative diseases are a complex group of neurological disorders that present a common hallmark the selective death of circumscribed groups of neurons. In accord, Parkinson's disease (PD) is characterized by a massive loss of melanized dopaminergic neurons in the pars compacta of the substantia nigra with a significant reduction of the striatal dopamine (DA) content (1) (Fig. 1). Cell death should be related to the activation of proapoptotic pathways. In the last years, many efforts were conducted to determine the etiology and pathophysiology of PD, although the mechanism underlying the selective neuron death remains unknown. Both genetic predisposition and environmental factors have been implicated in the etiology of PD (2). The presence of a familiar trait could account for the development of the illness in some populations. In this regard, a single base substitution in the a-synuclein gene in the 4q21-23 chromosome has been reported however, DNA mutations should be present...

Oxidative Stress In Pd

The substantia nigra neurons seem to be exquisitely sensitive to those stimuli which promote oxidative stress. In accord, under physiological conditions, protein oxidation in the substantia nigra is approximately twice that of any other brain area (2,7). In the last years, increased malondialdehyde levels, a metabolite of lipid peroxides, were detected in the substantia nigra of PD patients more recently, increased lipid peroxidation was proposed as a marker of oxidative stress in PD (8). In addition, increased iron concentration in substantia nigra of PD patients has been implicated in the progressive dopaminergic neuronal degeneration (9-11). In accord, experimental models confirmed that iron overload induces nigral degeneration, possibly through the production of hydroxyl radicals by the Fenton reaction In addition, oxidative stress depends not only on an increased oxygen free radical production but on the activities of antioxidant enzymes. Nigral neuron death was previously...

Cellular and Molecular Pathophysiology of Parkinsons Disease

Parkinson's disease (PD), the 2nd most common neurodegenerative disease after AD, similarly primarily affects older patients, with increasing incidence after age 60.21-23 As with AD, PD has both familial and sporadic forms. Clinically, PD manifests with a pill-rolling tremor, bradykinesia and rigidity.24 Postural instability may or may not ensue. Additionally, many patients experience dementia, autonomic dysfunction and neuropsychiatry symptoms.25 These features are shared with several other neurologic diseases, the most similar to PD being Dementia with Lewy Bodies (DLB).26 The symptomatology of PD is thought to occur due to loss of dopaminergic neurons in the nigrostriatal pathway, which will be discussed in detail below. As with AD, PD presents a challenge in treatment and incurs high costs to society in the provision of care for these patients. The cellular and molecular mechanisms thought to cause PD will be detailed briefly below. Histologically, PD and DLB show intraneuronal...

Therapeutic Potential of Radical Scavengers in Parkinsons Disease

PARKINSON'S DISEASE AND REACTIVE OXYGEN SPECIES Dopamine (DA) neurons within the substantial nigra may be particularly vulnerable to oxidant stress. Autooxidation or monoamine oxidase (MAO)-cata-lyzed DA oxidation could increase the likelihood of H2O2 formation with consequent Off production, by means of iron-catalyzed Fenton reaction. Indeed, postmortem studies conducted in brain from parkinsonian patients indicate that a state of oxidant stress exists in the substantial nigra pars compacta, as manifested by The reaction between H2O2, iron, and DA may be a source of endogenous 6-hydroxydopamine (6-OHDA) formation. This risk is increased in Parkinson's disease (PD) where the concentrations of iron in the striatum are relatively high. 6-OHDA by itself liberates iron from ferritin (5). In addition, 6-OHDA, as well as DA, have been shown to inhibit complex I and IV of the mitochondrial respiratory chain (6,7).

Neurodegenerative Disorders Alzheimers and Parkinsons Disease

In the elderly, age-related brain dysfunction and progressive occurrence of dementia are common causes of disability. Moreover, an increasing number of individuals are affected by Alzheimer's (AD) and Parkinson's Disease (PD). In both diseases, the underlying processes are a progressive pathologic degeneration of neurons, apoptotic cell death, and a substantial neuronal loss. This leads to dementia with cognitive and functional impairments and ultimately early death (108,109). Progressive formation of protein aggregates such as senile plaques (amyloid p-peptide protein) and neurofibrillary tangles (t protein) in AD patients and Lewy bodies (a-synuclein protein) in PD patients is concomitant with severe oxidative stress associated with altered metabolic pathways, inflammatory processes, and neurodegeneration (110,111). Epidemiologic evidence from human observational studies supports a protective role of vitamin E against AD. In a prospective study with 633 healthy older individuals...

Mitochondrial Electron Transport Chain and Oxidative Stress in pd

Tmrm Rotenone And Hek293 Cells

Deficiencies in mitochondrial electron transport chain underlie defects in energy metabolism and have been implicated in the neurodegenerative process. A reduction in complex I activity in PD is thought to cause bioenergetic dysfunction with subsequent loss of DA-ergic neurons 105 . Experimental evidence also points the involvement of certain genes, such as SNCA, Parkin, DJ-1, PINK1, GSTO1, LRRK2, and HTRA2 that encode corresponding proteins, including a-synuclein, E3 ubiquitin-protein ligase (parkin), transcriptional co-activator DJ-1, phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK-1), glutathione S-transferase omega 1 (GSTO1), leucine-rich repeat kinase 2 (LRRK2), and serine protease (HTRA2), in the pathogenesis of PD (Table 4). a-Synuclein is a small 140 amino acid presynaptic protein especially abundant in the brain. This protein is characterized by repetitive imperfect repeats (KTKEGV) throughout most of the amino-terminal half of the polypeptide, a hydrophobic...

Other Models of Parkinsons Disease PD

MPTP was discovered as a by-product of a failed illegal synthesis of meperidine analogs, when it caused a profound parkinsonian syndrome in drug addicts who self-administered the substance. The peripheral administration of the drug in monkeys and mice induces major mesencephalic DA cell loss and a similarly marked PD-like motor syndrome. As in the idiopathic disease, MPTP-induced PD is responsive to L-DOPA. MPTP continues to be widely used to model PD in mice and monkeys. Animals exhibit an acute parkinsonian syndrome that recovers rapidly after a single injection, and they need to be treated chronically to achieve stable bilateral cell loss, associated with profound parkinsonian debility, including akinesia, aphagia, and adipsia. As a consequence, unilateral lesions that retain the animals in better health are more suitable for long term studies of reparative and neuroprotective therapeutics, and can be achieved in monkeys by unilateral infusion of the toxin into the ascending...

What Has 6Hydroxydopamine Taught Us About Parkinsons Disease

6-Hydroxydopamine was first identified in 1959. By the early 1970s, this selective toxin for norepinephrine and dopamine neurons had become the principal tool by which laboratory studies of Parkinson's disease were performed, due largely to the pioneering work of Urban Ungerstedt and Norman Uretsky. The toxin has taught us an great deal about the possible causes, pathophysiology, and treatments of the disease. Although improved models are clearly required, some of which are being developed, even now half a century later 6-hydroxydopamine continues to play an important role in studies of parkinsonism. 6-OHDA 6-hydroxydopamine DOPA 3,4-dihydroxyphenylalanine DA - dopamine NE norepinephrine PD Parkinson's disease SN substantia nigra

Model Of Parkinsonism

Singlet Oxygen Disease

In patients with Parkinson's disease, the ensuing dopamine deficiency state Figure 6 Metallothioneins are low-molecular-weight zinc-binding proteins consisting of 25-30 cysteine, with no aromatic amino acids or disulfide bonds (top panel). The areas of the brain containing high contents of zinc such as the retina, the pineal gland, and the hippocampus synthesize unique isoforms of MT on a continuous basis. The four MT iso-forms are thought to provide the neurons and glial elements with mechanisms to distribute, donate, and sequester zinc at presynaptic terminals or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT (top panel). Electron spin resonance (ESR) spectra showing that the metallothionein isoforms I and II (0.3 mM) are able to scavenge hydroxyl radicals (1.75 x 1015 spins ml) generated in a Fenton reaction, as seen in the striatum of patients with Parkinson's disease (bottom panel). (Concepts from Ref....

Zigmond Parkinsons

An Essay on the Shaking Palsy. In Sherwood N, and Jones, ed. London 1817. 2 Foix C, Nicolesco J. Les noyaux gris centraux et la r gion M senc phalo-sous-optique. Suivi d'un appendice sur l'anatomie pathologique de la maladie de Parkinson. In Cie Me, ed. Anatomie c r brale. Paris 1925 508-39, as cited in 3 . 3 Saper CB. 'Like a thief in the night' the selectivity of degeneration in Parkinson's disease. Brain. 1999. 122 ( Pt 8) 1401-2. 5 Hornykiewicz O. Dopamine (3-hydroxytyramine) in the central nervous system and its relation to the Parkinson syndrome in man. . Deutsche medizinische Wochenschrift (1946). 1962. 87 1807-10. 11 Braak H, Braak E, Yilmazer D, Schultz C, de Vos RA, Jansen EN. Nigral and extranigral pathology in Parkinson's disease. J Neural Transm Suppl. 1995. 46 15-31. 12 Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004. 318 12134. 26 Fuxe K, Ungerstedt U....

What Is The Receptor Basis Of Antipsychotic Drugs Which Elicit Little Or No Parkinsonism

Anti Psychotic Drugs

The D2-blocking action of antipsychotic drugs commonly elicits Parkinsonism and other extrapyramidal signs. Clozapine and quetiapine, however, cause little or no extrapyramidal signs. Other antipsychotics may also cause few extrapyramidal signs if the dose is kept low. A dominant factor in determining whether a particular antipsychotic drug elicits Parkinsonism is whether it binds more tightly or more loosely than dopamine at the high-affinity state of the dopamine D2 receptor. This is illustrated in Figure 6. FIGURE 6 Antipsychotic drugs which bind more tightly than dopamine at the dopamine D2 receptor elicit Parkinsonism, while those which bind more loosely than dopamine elicit little or no Parkinsonism or other extrapyramidal clinical signs in patients. The radioligand-independent value for the dissociation constant of dopamine at the high-affinity state of the dopamine D2 receptor is 1.5 nM Data from Table 1. FIGURE 6 Antipsychotic drugs which bind more tightly than dopamine at...


The distinction should be made between the broad clinical syndrome of bradykinesia, rigidity, and tremor (parkinsonism) - which may result from several causes -and the idiopathic condition, Parkinson's disease (PD). Causes of parkinsonism are listed in Box 24.2. The relevance of the distinction between these conditions from the pain management perspective is that some of these conditions may be associated with somatosensory deficit, increasing the likelihood of neuropathic pain (although this has been proposed in idiopathic PD as well).

Parkinsons disease

A centrally active a1-adrenoceptor agonist, SDZ NVI-085 (Naphtoxazine), improved the performance of patients with Parkinson's Disease in some, but not all, tests for attentional deficits (Bedard etal. 1998). SDZ NVI-085 has shown activity in many of the animal assays for central a1-adrenoceptor activation. However, this compound has potent antagonist activity at 5-HT2 receptors (Lachnit etal. 1996) which could contribute to some of its CNS effects. The human striatum exhibits dense (1 -adrenoceptor binding and in MPTP treated monkeys it is clear that (-adrenoceptor antagonists reduce tremor. Overexpression of either wildtype or constitutively active a1b-adrenoceptors results in granulovacular neurodegeneration, beginning in the areas of the brain expressing highest levels of the a1b-adrenoceptor (cortex, cerebellum, and hypothalamus), and progressing to other brain areas with age (Zujik et al. 2000). These mice exhibit symptoms consistent with neuronal damage, including parkinsonian...

O Parkinson Disease

Motor Cortex Parkinson Disease

PD is a progressive neurodegenerative illness characterized by tremor, muscular rigidity, bradykinesia (slowness of movement), and postural imbalance.8 The incidence of PD is estimated to be about 1 in the general population older than 60 years of age.9 Although characterized as a neuro-muscular disorder, dementia also occurs at a much greater rate in PD patients over the normal age-matched population.10 Although the etiology of PD remains unknown, several factors appear to play a role, including the aging process, environmental chemicals, oxidative stress, and genetic aspects.9 The discovery that drug addicts exposed to the pyridine derivative (MPTP), a byproduct of synthetic heroin, developed a profound parkinsonian state led to intense study of the pathogenesis of PD.11,12 On the basis of investigations in the treatment of MPTP-treated primates, a working understanding of neurochemical basis of PD has developed. The primary motor control-related symptoms have shown to be the result...

Parkinson Disease

Another interesting application of the data regarding the functional role of 5-HT2C receptors in the basal ganglia is the possible use of 5-HT2C receptor antagonists in the treatment of Parkinson disease (Fox and Brotchie 1999 Nicholson and Brotchie 2002 Di Giovanni et al. 2006). The neural mechanisms underlying the generation of Parkinsonian symptoms are thought to involve reduced activation of primary motor and premotor cortex and supplementary motor areas, secondary to overactivation of the output regions of the basal ganglia, i.e., SNr and globus pallidus internus (GPi) (Albin et al. 1989), largely because of excessive excitatory drive from the subthalamic nucleus (STN), consequent to DA loss in the striatum (Nicholson and Brotchie 2002 Utter and Basso 2008). Hence, it is theoretically possible that antagonists at the 5-HT2C, which act directly to reduce STN neural activity, may have positive therapeutic benefits in acronymus Parkinson disease (PD). Therapy of Parkinson disease...

Timeline for Significant Catecholamine Related Events

Dopamine is neurotransmitter in brain dopaminergic pathways in brain identified reserpine depletion of brain catecholamines, with levodopa restoration of brain dopamine Low dopamine in substantia nigra & striatum in Parkinsonian patients Established effectiveness of levodopa for Parkinson's disease 1961 clinical trials initiated

Regulation of aaad activity

Even if AAAD is a regulated enzyme, there is no evidence supporting a rate limiting action for the synthesis of dopamine under normal circumstances. Despite commonalities in regulatory mechanisms and responses 41,57,66,71,75 often the pharmacological regulation of AAAD and tyrosine hydroxylase, the rate-limiting enzyme, in the striatum is discordant 42,60,74 suggesting 1) that AAAD might serve additional function(s) and or 2) that AAAD regulation might, in part, occur in extra-dopaminergic sites in striatum. Indeed, AAAD is the rate-limiting enzyme for the synthesis of trace amines 26 it is present in serotonergic and noradrenergic neurons and in a subset of AAAD+ neurons in striatum 76-78 and AAAD mRNA increases in the locus coeruleus and raphe nuclei, in addition to substantia nigra pars compacta and ventral tegmental area, after pharmacological manipulations 66 ,

Clinical Implications

When treating PD patients with exogenous L-DOPA, AAAD becomes the rate limiting step for the formation of dopamine and the potential to modulate the activity of the enzyme by pharmacological means should not be disregarded. We propose that enhancing and stabilizing AAAD activity might be an alternative approach to achieve and maintain optimal dopaminergic transmission with L-DOPA treatment, and AAAD inducers may prove to be useful L-DOPA adjuncts. Drugs that increase AAAD activity in the striatum enhance the formation of dopamine from L-DOPA, and are expected to decrease the dose of L-DOPA, smooth the rise and fall of striatal dopamine following intermittent administration of L-DOPA, and maintain relatively constant levels of intrasynaptic dopamine resulting, thus, to a more physiological receptor stimulation. Hence, L-DOPA decarboxylation enhancers could meet two important tenets for successful L-DOPA therapy 1) to use the least amount of drug that improves disability and 2) to...

The Partial Loss of DA Neurons Leads to a Variety of Compensatory Changes

The relationship between striatal DA levels and motor deficits in patients diagnosed with PD is not linear. As Oleh Hornykiewicz reported early on, DA levels in patients with PD are generally reduced by at least 80 . In the case of rats treated with intraventricular DA, we found the threshold to be even higher. This non-linearity is not unique to PD or animal models of DA deficiency, and has been described for other conditions, as well. Logically, there would seem to be several possible explanations for such non-linearity of neuronal loss versus symptoms. In the case of DA deficiency, we have identified three sets of explanations First, it is possible, though unlikely in my opinion, that there is simply a considerable redundancy of DA neurons and, as a result, the loss of a substantial proportion of these neurons requires no adjustment. Second, compensations might occur that allow the remaining DA neurons to adjust to the loss and maintain normal neuron-neuron communication. These...

The Pathophysiology of PD may Include Oxidative stress Inflammation andor Excitotoxicity

Studies of 6-OHDA models have provided a number of hints regarding the etiology of PD. Perhaps the most immediate suggestion is that PD involves oxidative stress. Indeed, there is a good deal of evidence that an early abnormality in brains of patients with PD is an increase in oxidative stress (see reviews 97,98,99 ). This includes reduced glutathione levels and glutathione-related enzymes 100,101 , increased iron 102 , decreased ferritin 103 , and increased 5-S-cysteinyl-dopamine 104 . Oxidative stress can be accompanied by many types of other insults including lipid peroxidation, protein and DNA damage, elevated iron levels, and mitochondrial impairments, each of which has been observed in postmortem samples from patients with PD. These findings may be relevant to 6-OHDA in several other ways. First, 6-OHDA can be formed endogenously from DA 105-107 and from DOPA 108,109 , the major drug used in the treatment of PD, and has been detected in human brain 110 . Second, like 6-OHDA, DA...

Classification of DAergic Receptors

D1-like receptors are coupled to stimulatory G protein (Gas), thereby activate AC through stimulatory G protein (Gas), whereas D2-like (D2, D3 and D4) receptors are coupled to AC via inhibitory G protein (Gai o) leading to inhibition of AC. In D1-like subfamily, both receptor subtypes are located post-synaptically and share similar pharmacological patterns, whereas in D2-like subfamily, receptors are located pre- and- post-synaptically and show variable effects (Table 1). In general, all subtypes in D2-like subfamily have higher affinity for anti-psychotic drugs and are involved in PD. There are major molecular differences between D1-like and D2-like subfamilies. Receptors in D1-like subfamily are intronless, contain short 3rd intracytosolic loops and have long C terminal tail. Receptors in D2-like subfamily contains introns in their respective coding regions thereby have a possibility for alternative splicing. In addition, they have long 3rd intracytosolic loops and short C terminal...

Dopaminemediated Learning Aging and pd

Sequential learning, involved with the processing of a variety of cognitive functions, such as linguistic expression, semantic sequencing, working memory, and procedural memory, is an important aspect of cognitive processing 88 . Sequential learning is impaired in PD patients, suggesting that altered dopamine neurotransmission may be responsible for serial reaction time learning deficits associated with this disease 89-90 . In animal studies, following neurotoxin, (MPTP)-mediated unilateral lesions in the striatum to deplete dopamine unilaterally in the striatum, show loss in learning sequential tasks 91-92 . Recent study using molecular imaging supports the notion that striatal dopamine is critical for motor sequential learning 88 . In PD, there is a decline in some forms of memory while leaving others relatively intact 98-99 . These patients suffer from impaired working memory and have problems in organizing and using new materials as well as applying strategies. Evidence indicates...

Pharmacogeneticspharmacogenomics in the

Treatment of pd anti-PD drugs, such as L-DOPA, with respect to adverse effects. Some PD patients exhibit L-DOPA- induced dyskinesias, whereas, others remain free despite treatment with L-DOPA. This may be due to changes in neuroplasticity among patients depending on their age and genetics 179 . In fact, genetic variability among individuals may affect differences in the expression of drug-metabolizing enzymes, receptors, and signaling proteins involved in the signal transduction pathways, resulting variability in drug responses 180 . The role of pharmacogenetics in the treatment of PD is relatively unexplored. Well-recognized drug-related complications (dopamine dysregulation syndrome) include hallucinations and psychosis 181 . The etiology of these complications is not clearly dose related, while the management can be difficult and needs to be tailored to the individualized therapy. Cholinergic and DA-ergic drugs may both influence cognitive function. Therefore, use of...

Conclusion and Direction for Future Studies

Dopamine, a major modulatory transmitter in the CNS, plays a crucial role in controlling multiple brain functions, including voluntary movement and a broad array of behavioral processes. DA-ergic neurons in the substantia nigra pars compacta are the main source of dopamine in the brain, and the selective loss of these neurons in this region leads to PD. This condition results in impairment in multiple motor and nonmotor features that significantly affect the quality of life. Current pharmacological treatments for PD are limited because they only offer symptomatic relief, but do not provide a cure. Therefore, these drugs are only effective in early stage of the disease. However, as disease progresses then complications predominate because current drugs do not prevent the continuing degeneration of DA-ergic neurons in the substantia nigra. Therefore, understanding of the exact molecular mechanism underlying the neurodegeneration of DA-ergic neurons in PD will promote the development of...

Polyunsaturated Fatty Acids Neurotransmission

Alterations in the expression of neurotransmitter receptors and levels of neurotransmitters along with the deficiency of DHA have been reported to occur in several neurodegenerative diseases including Alzheimer disease (AD) and Parkinson disease (PD). Thus, decrease in NMDA and AMPA receptors, along with glutamate transporter activity occurs in several brain regions from AD patients compared to brain tissue from age-matched control subjects 77-80 . In addition, a marked reduction in the expression of NR2A and NR2B subunit mRNA occurs in the hippocampus and entorhinal cortex in brains from AD patients 81 . These processes may induce changes in glutamate homeostasis in AD that may cause a major disturbance in Ca2+ homeostasis 82-83 , and the activity of Ca2+-dependent enzymes. Anomalous glutamatergic activity and changes in Ca2+ homeostasis leads to dementia and neuronal injury 56 . Similarly, marked alterations in dopamine levels have been reported to occur in PD. The abnormality in...

Biogenic Amines in Neurodegenerative and Neuropsychiatric Diseases

Neurodegenerative and neuropsychiatric diseases are a group of neurological disorders with heterogeneous clinical and pathological expressions affecting specific subsets of neurons in specific functional anatomic regions of brain and spinal cord. Thus, in AD neurodegeneration mainly occurs in the nucleus basalis and hippocampal area, whereas in PD dopaminergic neurons in the substantia nigra undergo neurodegeneration. In HD neurodegeneration occurs in striatal medium spiny neurons and motor neurons located in the anterior part of spinal cord degenerate in ALS. Although, the exact cause and molecular mechanism of neurodegenerative diseases are fully understood, but it is becoming increasingly evident that multiple factors and mechanisms may contribute to the pathogenesis of disorders 39 . The most important risk factors for neurodegenerative diseases are old age, positive family history, unhealthy life style, endogenous factors, and exposure to toxic environment 39 . Other risk factors...

Neurotransmitter Receptor Regulation of aaad

Studies with agonists suggest that dopamine receptor activation decreases enzyme activity, but the responses are variable and modest. In rodents, acute or chronic administration of D2-like agonists, particularly bromocryptine, suppresses the activity of AAAD in striatum while, the effect of D1-like agonists SKF 38393 is inconsistent 42,54,60,63,79 . Correspondingly, acute or chronic administration of L-DOPA 54,63 and inhibition of MAO A, which raises synaptic dopamine, also decreases AAAD activity in striatum 74,88 . Deprenyl attenuates AAAD activity in striatum at doses that inhibit both MAO B and MAO A 74 and elevates mRNA in the substantia nigra pars compacta and ventral tegmental area 70 . Diminution of AAAD activity by apomorphine has been observed using conversion of 3H DOPA into 3H dopamine in rat striatum in vivo 81 , and PET studies have shown a decrease in AAAD activity in the macaque striatum after MAO B inhibition 89 .

Trace Amine Associated Receptors

TAAR5 was previously identified as the human PNR (Putative Neurotransmitter Receptor) gene 3,6 . In the initial description of the identification of this gene, RNA transcripts were identified primarily in skeletal muscle of humans, with lower levels found in the amygdala, hippocampus, caudate nucleus, thalamus and hypothalamus 53 . A weak signal was also identified in the substantia nigra 53 . Expression in the kidney has also been reported 3 . Thus, the distribution of TAAR5 in the brain has similarities to that of TAAR1. Although expression levels in mouse olfactory epithelium were lower than other TAAR, mouse TAAR5 was shown to be activated by sexually mature male mouse urine 18 , suggesting that it may function as an olfactory receptor. Specifically, mouse TAAR5 appears to respond to tertiary amines (although not primary, secondary or quarternary), including trimethylamine 18 which is enriched in sexually mature, male mouse urine. In addition, a second tertiary amine,...

Perspective and Future Developments on Biogenic Amines in the CNS

Biogenic amines and their metabolites are important signaling molecules that regulate neural cell functions in the peripheral nervous system and central nervous system (CNS) in vertebrates and invertebrates. Alterations in biogenic amines levels along with excitotoxicity, elevation in ROS production, induction of neuroinflammation and loss of synapses are observed in neurodegenerative process in Alzheimer disease, Parkinson disease, and Huntington disease. The neuronal population that degenerates in above neurodegenerative diseases modulates movements, learning and memory, processing sensory information, and decision making processes. Although, alterations in biogenic amine levels may not be the primary event in the pathogenesis of neurodegenerative diseases, but biogenic amine-mediated oxidative stress and synaptic loss may contribute to dementia and other behavioral problems. Thus, normalization of biogenic amine levels through medication may correct some abnormal behavioral and...

Molecular Structure of aaad

Analysis of the neuronal promoter of the human, rat and mouse AAAD gene identified several potential positive and negative cis-acting elements 37 within the first 2.4 kb, which are highly conserved. The binding sites for transcription factors include, AP2, octamer-binding factor, Oct-1, N-Oct-3, SP1, NFY, GATA-1, HNF-1, HNF-3, CRE-BP, CP-1, Ptx3, NF-kB, SRF, EGR1, and Pet-1. Cooperation between some of these transcription factors has been found necessary for activation of the human AAAD neuronal promoter, which requires interaction between the NFY factor and the cell specific N-Oct-3 POU domain protein 38 . Several transcription factor binding sites detected in the AAAD promoter are also present in the tyrosine hydroxylase promoter, such as CRE-BP1, SP1, AP1, Ptx3, NF-kB, SRF, EGR1 and several POU octamers 39 , suggesting that the regulation of the transcription of the two enzymes can be coordinated. Of interest is the transcription factor Ptx3, which is restricted to the dopaminergic...

Historical Perspective

Interest in 1951 when Raab and Gigee showed that administered DOPA enhanced a catecholamine like substance in rat brain 14 , and subsequent studies revealed higher concentrations of dopamine in the brain than in other tissues 15 . At the same time, Carlsson et al. 16 demonstrated that DOPA, but not 5-hydroxytryphan, administration restored reserpine-induced motor deficits in experimental animals, and reported that dopamine was the major catecholamine in brain highly concentrated in the caudate nucleus 17 . Based on these observations, Carlsson postulated that parkinsonism was associated with loss of brain dopamine 17 . Perhaps the study that generated the most interest in brain dopamine was the observation by Ehringer and Hornykiewicz 18 that there was a severe dopamine loss in the caudate and putamen of PD patients. This was followed in the 1960s by reports from several research groups 19-21 that administered L- DOPA, the endogenous substrate for AAAD, alleviated the clinical...

Localization and Functional Implications of Dopamine Receptor Subtypes

Caudate putamen, dorsal striatum RD4 D4 mRNA expression at extremely low levels has been reported in rat striatum, but its expression is a controversial issue in the human striatum MD5 D5 receptor mRNA expression at low levels in the old-world monkey striatum. Nigrostriatal pathway (connects the substantia nigra with striatum) is particularly involved in the production of movement, therefore any disturbance in nigrostriatal dopamine function has been implicated in PD. The mesolimbic dopamine system originates in the ventral tegmental area and projects to several forebrain regions, including the nucleus accumbens. Mesocortical pathway connects the ventral tegmentum to the cerebral cortex, particularly the frontal lobes. Mesocortical dopamine system is essential for the normal cognitive function, motivational and emotional responses. Thus, disturbances in mesocortical dopamine functions have been implicated in both neuropsychiatric and neurodegenerative diseases. Caudate putamen, dorsal...

Transport Systems of Biogenic Amines

Na+, Cl-, and in some systems K+, to the reuptake of biogenic from the synaptic cleft to the nerve terminal. Dopamine transporter (DAT) requires two extracellular Na+ and one Cl- to cotransport with each dopamine molecule. Reuptake of monoamines into the nerve terminals and then into the synaptic vesicles allows recycling of same molecules. Biogenic amines interact with presynaptic and postsynaptic receptors after discharged from vesicles into the synaptic cleft by exocytosis following an action potential. Biogenic amines uptake transporters are targeted by major classes of antidepressant, psychostimulant and antihypertensive drugs 12,26,27 . DAT is the pharmacological target for widely abused psychostimulants such as cocaine, amphetamine and methamphetamine. Several classes of neurotoxins bind with these transporters and selectively poison specific neuronal groups 2831 . Catecholaminergic toxins such as 6-hydroxydopamine (6-OH dopamine) and 1-methyl-4-phenyl-piperidinium ion (MPP+)...

Aromatic LAmino Acid Decarboxylase

Aromatic L-amino acid decarboxylase (AAAD) is a required enzyme for the formation of catecholamines, indolamines and trace amines. AAAD gene and protein analyses have provided evidence for enzyme activity regulation at the transcriptional and post-translational levels. Extensive studies in neuronal tissues have demonstrated that AAAD activity is regulated by activation and induction, protein phosphorylation and gene transcription. A number of neurotransmitter receptors including dopamine (D1-4), glutamate (NMDA), serotonin (5-HT1A, 5-HT2A) and nicotinic acetylcholine receptors regulate AAAD activity in the rodent brain. Generally, receptor antagonists enhance AAAD activity while, agonists have no effect or diminish it. Second messenger systems, particularly cAMP, participate in the short- and long-term enzyme regulation in the brain. Following a lesion of nigrostriatal dopaminergic neurons, AAAD in striatum responds more robustly to pharmacological manipulations indicating ability for...


Three dopaminergic pathways are present in the brain The nigrostriatal pathway contains three-quarters of brain dopamine, has cell bodies originating in the substantia nigra and terminating in the corpus striatum, and is associated with motor control. The mesolimbic-mesocortical pathway, with cell bodies in the ventral tegmental area and projections to the limbic system, is involved with behavior, more specifically, reward and addiction defects in this system may account for some of the symptoms of schizophrenia. The cell bodies of the tuberoinfundibular pathway originate in the ventral hypothalamus and terminate in the anterior pituitary gland, and its activation is responsible for inhibition of the release of prolactin from the anterior pituitary 1,2,8 . Carlsson detected high levels of dopamine in the basal ganglia. Depletion of dopamine in the substantia nigra with reserpine caused Parkinsonian symptoms, which were alleviated by administration of the dopamine precursor levodopa....


In the peripheral autonomic nervous system, neurochemical transmission is relatively simple. Acetylcholine is the preganglionic neurotransmitter, while acetylcholine and norepinephrine are the neurotransmitter substances released from postganglionic cholinergic and adrenergic nerves, respectively. The situation is far more complicated and fascinating in the central nervous system. While there is a clear association between norepinephrine and depression and sleep, and between dopamine and Parkinson disease, schizophrenia, and drug dependence, these associations are no longer believed to be exclusive ones. Mounting evidence suggests that there are multiple etiologies of these conditions that involve some of the 40-50 neurotransmitters neuromodulators neurotropic factors present in the brain. Biogenic amines regulate a plethora of biologic responses. Further research into the molecular events associated with the actions of the various biogenic amines on specific subtype of receptors may...

Future Perspectives

Studies on animal model systems indicate that the phenotype changes in neurodegenerative diseases caused by environmental factors, such as exposure to toxins and the pathogenetic mechanism of the disease are only loosely linked. Thus, neurotoxins (MPTP or 6-OH dopamine)-mediated animal and cell culture models indicate that injections of neurotoxins damage neurons in a non-specific manner 61-65 . Many investigators, who have assigned neurodegeneration and function to a particular brain area on the basis of neurotoxin-mediated injury, may not be justified in their contention. Alterations caused by MPTP or 6-OH dopamine are similar but not identical to neurochemical and pathological changes found in human PD and the extent and complexity of cross talk among various neurotransmitters in MPTP or 6-OH dopamine- injected mice brain may differ considerably from abnormal cross talk that occurs in human PD. This suggests that neurotoxins-mediated neurodegeneration and behavioral changes are...

Dopamine Metabolism

Dopamine Metabolism

The repetitive transcranial magnetic stimulation (TMS) of the human dorsolateral prefrontal cortex leads to dopamine release in the ipsilateral caudate nucleus, which supports corticostriatal control of dopamine release in humans 16 . The repetitive TMS of the motor cortex induces dopamine release in the ipsilateral putamen 17 , confirming that dopamine release is focally restricted in healthy humans. However, measurement of dopamine release following cortical stimulation in early PD patients with evidence of unilateral motor symptoms shows that the amount of TMS-induced striatal dopamine release is less in the symptomatic hemisphere than in the contralateral hemisphere 18 , which may be due to advanced degeneration of DA-ergic nerve terminals and the failure of functional compensatory mechanisms. Thus, a possibility of in vivo expression of a loss of functional segregation of cortical information to the striatum gives an indirect evidence of abnormal corticostriatal...

Background History

Reserpine could deplete all stored monoamine transmitters 22 . The first specific study of the storage granule transporter in 1962 23 used adrenal chromaffin cells. Transporter specificity was limited uptake was coupled to ATP hydrolysis. Carlsson found that reserpine was the most potent inhibitor of vesicular amine transport 22 . Tetrabenazine and ketanserin are also potent inhibitors. Tetrabenazine has little effect on the peripheral vesicular monoamine transporter its depletion of CNS vesicular amine content lasts hours rather than days, unlike reserpine effects 24 . Once used extensively for treatment of psychosis and hypertension, reserpine is little used today because of many side effects, including depression and even suicide. Tetrabenazine is used today for chorea and other hyperkinetic movement disorders. It was never used for hypertension. The ketanserin derivative, (Cndihydrotetrabenazine nC-CIDTBZ) has been used as a ligand for positron emission tomography (PET scanning)...

Future Directions

Where to go from here First and foremost we need much better interventions. We need to develop treatments that reduce a more complete range of parkinsonian symptoms -physiological and psychiatric, as well as motor - and that do not show tolerance or dyskinesias. We need treatments that reduce disease progression. And ultimately we need treatments that actually prevent the appearance of the disease. If we are to accomplish these goals, then a second set of future requirements is a much more complete understanding of the causes of PD - genetic factors, environmental influences, and cellular mechanisms,


Dopaminergic pathways and two families of dopamine receptors (D1-like and D2-like) in the brain that influence motor function, behavior, reward and drug dependence, attention-deficit-hyperactivity disorder, and prolactin release. A depletion of dopamine exists in the substantia nigra and striatum in Parkinson disease. One leading model of schizophrenia suggests that schizophrenia is associated with an increase in the functional activity of dopamine in the limbic system. Typical antipsychotic agents are potent D2-antagonists, while atypical antipsychotics have dopamine and serotonin receptor blocking actions.

Arrestin Receptor Interface

Selective reduction of arrestin interactions with a particular GPCR would slow down its desensitization and internalization, thereby enhancing and prolonging G protein-mediated signaling. This kind of intervention has therapeutic potential in conditions usually treated with GPCR agonists (e.g., asthma) and agonist precursors (e.g., Parkinson's disease) because it counteracts the very process that severely

[3HMesulergine An Interesting Molecule 121 CU32085 A Semisynthetic Ergot Compound

It is in this conceptual environment that the discovery of the 5-HT1C (later 5-HT2C) receptors took place at Sandoz (now Novartis) in Basel, Switzerland. Sandoz had a long tradition of working with ergot derivatives with multiple useful pharmacological activities. Semisynthetic ergot compounds were being developed at the end of the seventies in many therapeutic areas. One of those was CU32085, also known as mesulergine. This compound presented interesting dopaminomimetic activities in animal models and was being developed as an antiparkinsonian drug. Binding studies carried out by Annemarie Closse at Daniel Hauser's group, with the technical help of Armand Wanner, using 3H mesulergine, surprisingly showed a potent binding of this compound to 5-HT2 receptors in the rat brain (Closse 1983).

Membrane Transporters In Therapeutic Drug Responses

PHARMACODYNAMICS TRANSPORTERS AS DRUG TARGETS Membrane transporters are the targets of many drugs. For example, neurotransmitter transporters are the targets for drugs used in the treatment of neuropsychiatric disorders. SERT (SLC6A4) is a target for the selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs. Other neurotrans-mitter reuptake transporters serve as drug targets for the tricyclic antidepressants, amphetamines (including amphetamine-like drugs used in the treatment of attention deficit disorder in children), and anticonvulsants. These transporters also may be involved in the pathogenesis of neuropsychi-atric disorders, including Alzheimer's and Parkinson's diseases. Transporters that are nonneuronal also may be potential drug targets (e.g., cholesterol transporters in cardiovascular disease, nucleo-side transporters in cancers, glucose transporters in metabolic syndromes, and Na+-H+ antiporters in hypertension).

Genetic Variation In Membrane Transporters Implications For Clinical Drug Response

Inherited disorders of membrane transport have been identified (Tables 2-2 and 2-3), and polymorphisms in membrane transporters that play a role in drug response are yielding new insights in pharmacogenetics (see Chapter 4). The most widely studied drug transporter is P-glycoprotein (MDR1, ABCB1) the ABCB1 genotype is associated with responses to anticancer drugs, antiviral agents, immunosuppressants, antihistamines, cardiac glycosides, and anticonvulsants. ABCB1 SNPs also have been associated with tacrolimus and nortriptyline neurotoxicity and susceptibility for developing ulcerative colitis, renal cell carcinoma, and Parkinson's disease.

Looking Farther Ahead The Combination of Conventional and Unconventional

The signaling of the mutant receptor back to normal levels. Similarly, arrestins with anti-proliferative or simply pro-apoptotic signaling bias selectively expressed in cancerous cells by means of appropriate targeting vectors would likely solve the existing problem without creating new ones after all, the ideal therapeutic outcome is the death of every cancer cell in the body. In contrast, it will be necessary to control the effectiveness of arrestin mutants with pro-survival signaling bias, the expression of which in affected neurons may be beneficial in neurodegenerative disorders, such as Alzheimer's and Parkinson's. Excessive signaling shift in that direction may lead to cell dedifferentiation, which would be just as harmful as the disease itself.

The Independence of 5HT1C Sites with Respect to 5HT and 5HTJR

In addition, 3H OH-DPAT was shown to label a more restricted population of sites in the brain than 3H 5-HT (Pazos and Palacios 1985 Hoyer et al. 1986a). By using 3H 5-HT and 3H mesulergine as radioligands and 8-OH-DPAT, the beta-blocker (SDZ 21-009, a very useful compound picked by Guenter Engel), and mesulergine itself as the main displacers, we succeeded in identifying anatomical areas particularly enriched in each 5-HT1 subtype Some examples are the dentate gyrus of the hippocampus for the 5-HT1A, the substantia nigra (reticular) for the 5-HT1B, and of course, the choroid plexus for the new 5-HT1C. These studies contributed to establishing the independence of 5-HT1C sites with respect to 5-HT1A and 5-HT1B. 1C

Using Other Compounds

Production in hippocampus (Markstein et al. 1986 Schoeffter and Hoyer 1989a) in the substantia nigra (Schoeffter and Hoyer 1989b), stimulation of PLC production in choroid plexus (Hoyer et al. 1989) or in smooth muscle cells, and contraction or relaxation of various vessels (Hoyer 1988a).

Geneticallyengineered cells

Potential applications in amyotrophic lateral sclerosis, dwarfism, pain treatment, IgG1 plasmacytosis, hemophilia B, Parkinsonism and axotomized septal cholinergic neurons, tumor suppression and other areas (Basic etal., 1996 Tan etal., 1996 Al-Hendy etal., 1996 Okada et al., 1997 Dalle et al., 1999 Saitoh etal., 1995 Hagihara et al., 1997 Winn etal., 1994 Aebischer et al., 1996 Bloch et al., 2004 Bachoud-Levi et al., 2000 Xu et al., 2002 Cirone et al., 2002). To avoid the need for implantation, we studied the oral use of artificial cells containing genetically-engineered nonpathogenic E. coli DH5 cells to lower systemic urea in renal failure rats (Prakash and Chang, 1996 Chang, 1997).

Purinergic Neurotransmission Focus On Adenosine

Four adenosine receptors have been cloned (A1, A2A, A2B, and A3), each of which exhibits unique tissue distribution, ligand binding affinity (nanomolar range), and signal transduction mechanisms (Cooper et al. 2001). Currently available data suggest that the high-affinity adenosine receptors (A1 and A2A) may be activated under normal physiological conditions, whereas in pathological states such as hypoxia and inflammation (in which high adenosine concentrations micromolar range are present), low-affinity A2B and A3 receptors are also activated. A2B receptors are expressed in low levels in the brain but are ubiquitous in the rest of the body, whereas A2A receptors are found in high concentrations in areas of the brain that receive dopaminergic projections (i.e., striatum, nucleus accumbens, and olfactory tubercle) (Nestler et al. 2001). Given this receptor's distribution and the inverse relationship between DA and adenosine, it has been postulated that A2A antagonists may have some...

Pharmacological Properties

Although Parkinson's disease (PD) is classified as a movement disorder, it should also be considered as a neuro-behavioral'' disorder. The diagnosis of PD is based on the presence of clinical criteria having to do purely with movements and the absence of exclusionary or atypical features, laboratory tests being of little or no value. Nevertheless, the most devastating aspects of PD are more often behavioral. Other nonmotor problems, such as sympathetic dysfunction and sleep disorders have only attracted clinical and research attention in the last few years. For perspective two studies, one a large retrospective review in Australia, and the other, a county wide prospective study with formal testing in Norway, both concluded that by the time of death, 80 of PD patients are demented. In addition, at any point in time, somewhere between 30 and 50 are depressed 40 suffer from anxiety 40 with apathy 30 of drug treated patients with visual hallucinations 5-10 of drug treated patients with...

Oxidant Stressrelated Pathologies

One of the most important targets for oxidant-related damage is the brain. For one, oxidative stress is associated with a wide range of brain pathologies, many of which are mediated by excitotoxicity. Excitotoxicity is thought to play an important role in neurodegeneration and is associated with the generation of reactive oxygen species (Bondy and LeBel, 1993). Neuronal loss through neurodegeneration underlies many neural disorders and diseases, including Alzheimer's disease, stroke and ischemia, seizure activity, Huntington's disease, aging, Parkinson's disease, and more. Second, the high lipid content of the brain makes lipid peroxides and aldehyde byproducts likely triggers for cellular damage and gene modulation. Finally, brain damage affects other parts of the body, e.g., muscular function. The oxidant-inducible genes heme oxygenase and c-fos are associated with brain damage and dysfunction as is the antioxidant gene Cu,Zn-superoxide dismu-

Species Differences in 5HT2C Receptors Distribution Rodent Versus Human and Nonhuman Primates

There are also differences in 3H mesulergine binding sites in human brain when compared with monkey (Macaca fascicularis) brain. High densities of binding sites are observed in the human globus pallidus and substantia nigra (Pazos et al. 1987), whereas they are absent in monkey globus pallidus and low in substantia nigra (Lopez-Gimenez et al. 2001a). In monkey neocortex, low levels of 3H mesulergine binding sites are detected on layer V, whereas in human cortical areas binding sites are located predominately in layer III. Although the distribution of 5-HT2C receptor mRNA in monkey brain (Lopez-Gimenez et al. 2001a) is very similar to that in rat (Eberle-Wang et al. 1997 Pompeiano et al. 1994 Wright et al. 1995), mouse (Mengod et al. 1990a), and human brain (Pasqualetti et al. 1999), there are some differences. In the neocortex of mouse and rat the 5-HT2C receptor mRNA are found at detectable levels only in prefrontal, cingulate, and retrosplenial cortices, whereas in monkey, mRNA is...

Apomorphine Definition

Apomorphine is a drug used to treat impairments in motor function (tremor, slow movement, and difficulty walking and speaking) in Parkinson's patients. It is sometimes used for erectile dysfunction. In larger doses, it has emetic effects and was used in aversion therapies. It is a nonspecific dopamine agonist with actions at several subtypes of dopamine receptors, both presynaptic and postsynaptic. As a pharmacological tool for probing the function of dopamine receptors, it has been largely replaced by more selective substances. It does not have morphine-like effects and does not interact with opioid receptors.

Animal Models of Neurological Disease

For years researchers have turned to animal models to recreate neurological pathologies and their subsequent symptoms to understand the mechanisms behind human neurological diseases, as well as possible therapeutic strategies. Animals with short generation times and well-documented genomes that are easily manipulated have provided excellent model systems.1 Rodents are commonly utilized as models for Parkinson's disease (PD), cerebral ischemia, Huntington's disease (HD) and Alzheimer's disease (AD), among others.2 Hypokinetic and hyperkinetic movement disorders have also been successfully modeled in nonhuman primates.3 However, many remain skeptical regarding the use of phylogenetically lower species to study human disease. Whereas genetic and molecular basis of disease can be evaluated in lower organisms, it would seem that pathophysiological symptoms and success of possible treatments be best tested in higher, more closely related organisms such as nonhuman primates. However,...

HT2C Receptors and the Dopaminergic Receptors System

Dopaminergic nuclei, such as retrorubral area, substantia nigra pars compacta, ventral tegmental area and periaqueductal gray, and dorsal striatum and nucleus accumbens, express 5-HT2C receptor mRNA (Eberle-Wang et al. 1997 Mengod et al. 1990a Pompeiano et al. 1994 Ward and Dorsa 1996). Pharmacological activation of 5-HT2C receptors inhibits firing rates of ventral tegmental area neurons and dopamine release within the nucleus accumbens (Prisco et al. 1994 Di Giovanni et al. 1999 Di Matteo et al. 1998). The implication of 5-HT2C receptors in the regulation of nigrostriatal dopaminergic function has been a subject of debate mainly due to controversial results obtained with different 5-HT2C receptor acting molecules (Di Matteo et al. 2001 Porras et al. 2002 De Deurwaerdere et al. 2004 Navailles et al. 2004). Very recently (Abdallah et al. 2009) by using the 5-HT2C receptor null mutant mice, previously generated by Tecott and collaborators (Tecott et al. 1995), it has been studied in a...

Comparative Phylogenetic Distribution

NAAG in groups with known neurotransmitters. NAAG is colocalized with virtually all major neurotransmitters including GABA (Figure 8), acetylcholine in the vertical limb of the diagonal band of Broca (A), norepinephrine in the locus coeruleus (B), dopamine in the compact part of the substantia nigra (C) and serotonin in the raphe (D). Bar 100 m. Figure 9. NAAG in groups with known neurotransmitters. NAAG is colocalized with virtually all major neurotransmitters including GABA (Figure 8), acetylcholine in the vertical limb of the diagonal band of Broca (A), norepinephrine in the locus coeruleus (B), dopamine in the compact part of the substantia nigra (C) and serotonin in the raphe (D). Bar 100 m.

The National Academies

EMMELINE EDWARDS, NIH Neuroscience Blueprint RICHARD FRANK, GE Healthcare, Inc. MYRON GUTTMAN, National Science Foundation RICHARD HODES, National Institute on Aging KATIE HOOD, Michael J. Fox Foundation for Parkinson's Research STEVEN E. HYMAN, Harvard University THOMAS INSEL, National Institute of Mental Health DANIEL JAVITT, Nathan Kline Institute for Psychiatric Research STORY LANDIS, National Institute of Neurological Disorders and Stroke

Small Molecule Drug Delivery

An alternative delivery strategy for small molecules is based on the presence of the nutrient transporters. Drugs that are structurally similar to substrates of a carrier system can undergo facilitated brain uptake as pseudoneutrients. The best example of this is the therapeutic use of L-DOPA in Parkinson's disease. Unlike the neurotransmitter dopamine itself, which cannot cross the BBB in significant amounts, its precursor L-DOPA is a substrate for LAT, the transporter of large neutral amino acids 56 . Its uptake by the brain is saturable, and subject to competition by the other substrates of the carrier present in plasma.

Mechanisms Of Induction Of Apoptosis

We have also used MPTP, which is to induce oxidative stress and neurodegeneration in the brain, which is partly due to its ability to interfere with mitochondrial function (23). MPTP has been used to model Parkinson's disease in animals. MPTP is bioactivated by monoamine oxidase B to MPP+, which is 1-methyl-4-phenylpyridine, such that monoamine oxidase B knock-out mice, which do not express the enzyme, are resistant to MPTP toxicity (24). MPP+ is reduced by a number of different enzymes including tyrosine hydroxylase, monoamine oxidase, xanthine dehydrogenase, aldehyde dehydrogenase, lipoamide dehydrogenase, and NADH dehydrogenase (25-27). The result of the two-electron reduction is the induction of oxygen radical formation and redox cycling of MPP + . MPTP administration causes brain levels of GSH to change, GSSG levels to increase, and protein sulfhydryl levels to decrease in some brain regions (26,27). GSSG reductase is involved in protection against MPTP toxicity (28,29), since it...

Biosynthesis of NADA and other endocannabinoids more questions than answers

Partly due to the fact that their roles as endocannabinoids have not yet been conclusively confirmed, little information still exists on the biosynthetic and catabolic pathways of NADA, virodhamine and noladin ether. Regarding the latter compound, after the initial work of Hanus et al. (2001), two more studies have reported contrasting results on its actual occurrence in brain tissue (Fezza et al. 2002 Oka et al. 2003), and this may have somehow hampered the performance of further studies on noladin ether's metabolic pathways. However, it was clearly established that this putative endocannabinoid is not produced in intact mouse neuroblastoma cells from arachidonic acid incorporated into phospholipids and after ionomycin stimulation, i.e. using conditions leading to the biosynthesis of large amounts of 2-AG (Fezza et al. 2002). As to NADA, strong evidence has been reported against this compound being produced from the metabolism of N-arachidonoyl-tyrosine and using the same enzymes...

Nigrostriatal And Mesolimbic Dopaminergic Systems

Dopamine's role as a major central neurotransmitter, and its involvement in motor activity, were confirmed when it was found that one area of the brain in particular, the caudate nucleus, contained the highest concentration of DA of any tissue in the body (Bertler and Rosengren, 1959 Sano et al., 1959). This brain area was already known to mediate the extrapyramidal side effects of several drugs, and the experiments of Vander Eecken et al. (1960) and Adams et al. (1964) showed that patients with movement disorders had loss of tissue in the caudate nucleus. It was also discovered from post-mortem samples that there were much lower levels of DA in the caudate putamen (striatum) as well as the cell bodies of the substantia nigra (SN) in Parkinson's patients than in these same brain areas from normal individuals (Ehringer and Hornykiewicz, 1960). Within two years the efficacy of using L-DOPA to alleviate the symptoms of Parkinson's disease was reported by Birkmayer and Hornykiewicz (1961)...

Gene Therapy Of Remyelination Future Applications

Safety study using a growth factor named ciliary neurotrophic factor (CNTF) has been already performed in humans affected by amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of the motor neurons.37 This study showed that introduction of heterologous genes coding for CNTF into the CSF using encapsulated genetically modified CNTF-producing myoblasts is feasible and non-toxic. Moreover, experiments aimed at delivering genes coding for other neurotropic factors have also been performed in non-human primates affected by an experimental model of Parkinson's disease in which therapeutic effects have been observed without any side-effects related to the procedure or to the vector toxicity.

Muscarinic M4 Receptors

Parkinson's disease is a neurodegenerative characterized by slow movements, muscular rigidity, tremor, and balance disturbances. These symptoms arise from the loss of dopaminergic neurons projecting to the striatum, causing an imbalance between the cholinergic and dopaminergic systems, such that the former dominates. Nonselective muscarinic antagonists are effective in treating the disease, although side effects limit their use. Transgenic mice lacking the M4 receptor show increased locomotor activity and an enhancement of dopamine D1 receptor-mediated effects (Gomeza et al. 1999). It is likely that the striatal M4 receptors exert an inhibitory action on dopamine D1 receptor function. Consequently, selective M4 antagonists have been developed for the treatment of Parkinson's disease, including benzoxazines such as PD 0298029, the latter of which has a favorable pharmacoki-netic profile and good bioavailability in the clinic (Bohme et al. 2002).

Application of Proteins and Genes as Targets to Accelerate Drug Discovery and Development

The identification in the 1980s of the gene thought to be responsible for cystic fibrosis took researchers about nine years to discover, whereas the gene responsible for Parkinson's disease was recently identified within a period of weeks. This extraordinary leap in the ability to associate a

For interactions among glutamate and da receptor subtypes

The striatum is the main input structure of the basal ganglia. It is a central region where afferents from the cerebral cortex, thalamus, and substantia nigra converge and interact. Glutamate is released from cortical and, to a lesser extent, thalamic terminals.1112 DA is released from nigrostriatal terminals.13 Because glutamate and DA inputs terminate on the same spines of striatal medium-sized spiny neurons (MSSNs), these sites offer the potential for physiological interactions between the glutamate and DA transmitter systems.14 Morphological evidence demonstrates the presence of synaptic complexes formed by axospinous contacts

Fatty acid amide hydrolase AEA degradation and beyond

Despite the wide substrate selectivity of FAAH, this enzyme certainly plays a role in regulating the activity of CB1 receptors, as shown by the several immunohistochemical data pointing to the complementary distribution of the two proteins in the CNS. In fact, CBx and FAAH are mostly localized at the pre- and post-synaptic level, respectively, in many (but not all) brain areas (Egertova et al. 2003 Gulyas et al. 2004). In these regions, FAAH may regulate post-synaptic levels of anandamide (Egertova et al. 2003), whereas in regions such as the globus pallidus and substantia nigra pars reticulata, CB1 receptors are not associated with FAAH expression. In these brain regions the control over endocannabinoid signalling may be less restricted than in regions enriched with FAAH. Finally, in those brain regions where FAAH-immunoreactive neurons occur in the absence of CB1, the enzyme may be involved in the regulation of endocannabinoid actions at other endocannabinoid receptors (Di Marzo et...

Potential Aluminum Toxicity

2 In a number of OTC drugs, aluminum is a major component. In fact, excessive use of aluminum-containing antacids, available as OTC medication, could contribute quantitatively to aluminum exposure of humans. Hence, a warning on potential dangers from aluminum-containing drugs serves to raise consciousness against their unsupervised use. Potential links of aluminum with neurodiseases, like idiopathic Parkinson's disease, have also been reported.62

Ethical Considerations

Embryos for medical purposes is ethical. Promising experience has been gained in the last decade with transplantation of fetal mesencephalic tissue into patients suffering from advanced Parkinson's disease.72,73 The large amount of fetal tissue that is required for this technique poses a major obstacle to its widespread use. In addition to the basic ethical discussion on the use of abortion material for medical purposes, concerns were raised that the practice of embryonic tissue transplantation will increase the pressure to perform abortions and create a black market in which pregnancy and aborted tissues will be sold to the highest bidder. The development of stem cell lines that are expanded in vitro to create an almost unlimited source of cells for transplantation may solve some of the ethical issues at stake. As in other cases where medical and scientific advances have found society without the means to deal with their ethical, legal and social consequences, it is important to...

Of D1nmda Occurs Receptor Interactions

Reynolds et al.58 measured responses to cortical afferents before and after intracranial self-stimulation of the substantia nigra that would release DA. Such stimulation of DA cells with behaviorally reinforcing parameters induces potentiation of glutamatergic corticostriatal synapses that is blocked by administration of a D1 receptor antagonist. Timing is an important requirement for this type of synaptic plasticity because DA release should occur before excitatory afferents are activated in order to induce potentiation.59 It is tempting to speculate that if D1 receptors are activated first, G protein- and Ca2+-dependent oligomerization of D1-NMDARs occurs, providing a regulated delivery of these complexes to plasma membranes, dendritic spines, or both. Massive DA release due to unexpected reward enhances the relevance of the stimulus by potentiating NMDA responses. This process is particularly important in MSSNs enriched with D1 receptors.

Choosing the Experimental Animal

Since NSC therapy has yet to be approved for human clinical trials, experimental animals must be used. Mice are generally used for several reasons. First, as mammals, they share many homologous features with humans which will be very important in years to come when these studies are translated into clinical trials. Since the murine genome has already been sequenced, one can easily correlate the murine genes and their human homologs. Additionally, we now have engineered many murine lines expressing specific models of human disease or CNS insult such as lesions, tumors, parkinsonism and global demyelination (as observed in multiple sclerosis and many congenital metabolic disorders). Logistically, mice are small, inexpensive and easily maintained. They have quick gestations and high pregnancy rates resulting in higher and more quicker yields than in other animal models. Lastly, mice can be exploited in a manner often considered unethical in humans and more highly developed animals.

In the nervous system

An emerging role of TRPV1 in regulating movement has recently attracted attention. It appears that in the basal ganglia (a region important for controlling movement) anandamide activation of TRPV1 resulted in decreased dopamine release and reduced movement of rodents (de Lago et al., 2004 Lee et al., 2006 Tzavara et al., 2006). Conversely, in the substantia nigra anandamide increased spontaneous excitatory postsynaptic currents through presynaptic TRPV1 receptors and release of glutamate onto dopaminergic neurons (Marinelli et al., 2003). In agreement with this, anandamide increased NMDA-induced excitatory postsynaptic currents observed in dopaminergic synapses of the ventral tegmental region in rat slices are mediated by TRPV1 activation. Interestingly, when TRPV1 receptor activity was blocked the canonical inhibitory effect ofanandamide acting through CB1 receptors was observed suggesting these pathways may act in competition (Melis et al., 2004).

Genetic Manipulations Of Danmda Receptor Interactions

Although all MSSNs are GABAergic, they differ in expression of DA receptor subtypes, peptide contents, and projection targets.79 Two major neuronal subpopulations of MSSNs have been described. One projects primarily to the substantia nigra pars reticulata and the internal segment of the globus pallidus (direct pathway). The other subpopulation projects primarily to the external segment of the globus pallidus (indirect pathway).80 MSSNs originating the direct pathway mainly express D1 receptors and colocalize substance P. MSSNs originating the indirect pathway mainly express D2 receptors and colocalize enkephalin although some overlap exists.81-83

Choosing the Surgical Procedure

In focal CNS disorders, such as Parkinson's disease or spinal cord injuries (SCI), intralesional administration of NSCs are perhaps best suited to treat local cell deficiencies. ES-cell-derived neuronal precursors have been shown to induce dopaminergic neuron differentiation in the substantia nigra to treat parkinsonism in rodent model brains.66,67 In SCI or experimental ischemic rodent models, intralesionally-transplanted aNSCs integrated with host tissue, differentiated preferentially into glial cells, released neurotrophic growth factors (i.e., BDNF, glial-derived neurotrophic factor (GDNF) and nerve growth factor (NGF)) and facilitated neurogenesis while inhibiting astrocytosis (the abnormal destruction of nearby neurons, generally caused by hypoglycemia or oxygen deprivation). Overall motor recovery was observed.17,68-70 In another experiment involving chemically demyelinated rat spinal cords, ES cells not only integrated and differentiated within the lesion, but in fact were...

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In turn, L-DOPA is converted to dopamine by dopa decarboxylase either in the capillary endothelium or in dopaminergic neurons. Thus, administration of L-DOPA increases the substrate for dopamine and results in increased dopamine synthesis and release. Although L-DOPA passes the blood-brain barrier, L-DOPA is rapidly converted into dopamine in the blood when administered orally. This renders approximately 95 of it unable to enter the CNS, while the remaining 5 penetrates and is then converted to dopamine. Although this was enough to alleviate parkinsonian symptoms, the large amounts of circulating dopamine created the side effect of nausea. The next step of progress came with the drug carbidopa, which inhibits peripheral DOPA decarboxylase. Thus, conversion of L-DOPA to dopamine is supressed in circulation, but continues unhindered centrally because carbidopa does not cross the blood-brain barrier. This effectively reduces the necessary dose of L-DOPA by 75 . L-DOPA and...

Dimers May Allow for Conformational Switches Underlying Receptor Cross Talk and Other Forms of Allosterism

At first glance, the model depicted in Fig. 4.2c does not seem to have any specific merit in providing a parsimonious explanation. With a little imagination, it is possible to draw ever- more complicated arrangements, in which arrays of receptors are confronted with tubes of G proteins of various stoichi-ometries. The arrangement in Fig. 4.2c specifically suffers from the drawback that it does not solve the foot size shoe size problem 20 - But, it does have the advantage that it can account for mutually antagonistic cross-talk in het-erodimeric receptors. Such a finding has been observed for the A2A adenosine receptor and the D2 dopamine receptor, which can assemble into a heterodi-mer 67, 68 . This dimer formation is thought to be of interest for the treatment of Parkinson's disease, because the mutual inhibition of the two receptors is predicted to have an impact on movement control by the corpus striatum activation of the A2A receptor impedes D2 receptor coupling and is thus...

Use of Cholinesterase Inhibitors in Other Dementia Related Illnesses

Besides their use in Alzheimer's disease, cholinesterase inhibitors have been extended to treat other dementias and related illnesses, which may include vascular dementia, dementia with Lewy Bodies, dementia associated with Parkinson's, mild cognitive impairment, and mixed dementia. Research is particularly important in this area since it is not uncommon for Alzheimer's disease to be co-morbid with other types of dementia. Therefore, it is important to devote a section briefly discussing recent findings and the use of Parkinson's disease is a common neurodegenerative disease occurring usually in the elderly. Often comorbid with Parkinson's disease is dementia, which is associated with cholinergic deficits and occurs in 30-50 of patients with Parkinson's disease 81 . Emre and colleagues randomized 541 patients who had Parkinson's disease with dementia to either rivastigmine or placebo. Their result showed that patients who were on rivastigmine had statistically significant improvement...

Neurological disorders

NR-mediated glutamate toxicity is considered a common pathological pathway of many acute and chronic neurological disorders such as brain trauma, brain ischemia, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, AIDS dementia, and Lou Gehrig's disease.6-810136 Since NR function and activity are determined by a specific set of NR genes expressed in a given cell and by the level of that expression, abnormal transcription of the NR genes may contribute to NR pathological effects. Reduced expression of the NR genes was found in the brains of patients with other neurodegenerative disorders as well. Alzheimer's disease patients showed reduced expression of the NR1 and NR2B gene in the hippocampus.151 Parkinson's patients exhibited reduced NR1 expression in the striatum and in the superficial layers of the prefrontal cortex.152 Whether polymorphisms of the regulatory regions also play a role in this altered NR gene expression is an interesting question that...

The DrugH Antiporter1 DHA1 12 Spanner Family

Experimental studies have indicated that amphetamine-type agents interact with the VMAT2 and deplete vesicular neurotransmitters via a carrier-mediated exchange mechanism 151 . The cytoplasmic levels of transmitter are increased due to disruption of the vesicular transmitter storage of transmitter, such that more neurotransmitter is available for release by transporter-mediated exchange 151 . It has been proposed, based on its functions as a critical regulator of neurotransmitter disposition within the brain, that the VMAT2 transporter might be a possible target for drugs used in addictive disorders, Parkinson's disease and schizophrenia 152,153 .

Fatigue As A Symptom In

CFS is a true syndrome, not a single disease. As with other neurological syndromes (Parkinsonian, Guillain-Barre or carpal tunnel), the etio-pathogene-sis of CFS is diverse, probably multifactorial, with stress and systemic viral infections being the two commonest factors.3 However, irrespective of the precise pathogenic mechanism of CFS, fatigue symptoms are very similar across all CFS patients and are indistinguishable from the symptoms of fatigue experienced by patients with certain neuro logical disorders such as multiple sclerosis (MS) or Parkinson's disease.4 Fatigue symptoms in MS are very similar to CFS, and there is additional evidence to support a common pathophysiology of fatigue in both these disorders.56 In addition, both MS and CFS patients with fatigue have a significantly lower frequency of psychiatric diagnosis than the depressed controls.7

Mesotelencephalic Dopamine Systems

Studies in rats that utilized histochemical fluorescence techniques demonstrated that the dopaminergic innervation of the forebrain arises largely from the ventral mesencephalon (VM) and that subcortical structures, such as the caudate nucleus, are innervated by lateral regions of the VM, the substantia nigra pars compacta.19 Subsequently, dopaminergic innervation of the frontal cortex was also identified,20 and the cortical dopamine terminals were reported to arise largely from the medial regions of the VM (ventral tegmental area).21 More recently, the mesencephalic origin of dopamine innervation of the cerebral cortex and caudate-putamen in the monkey has been shown to be much more widespread and overlapping, not following the anatomical distinctions present in the rodent.22

Nonreceptormediated Glutamate Neurotoxicity

Cytotoxicity due to GSH depletion is not unique to glutamate. Other agents that deplete cells of GSH have also been shown to cause cell death. Agents that target y-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, are particularly cytotoxic. Treatment of cells with L-buthionine-(s,R)-sulfoximine (BSO), an inhibitor of GCS, and transfection of cells with GCS antisense DNA leads to GSH depletion and cell death (30,118,119). GSH-depleting agents do not, however, always completely mimic the effects of glutamate. For example, glutamate treatment of C6 glial cells resulted in GSH depletion and cell death within 24 h (120). BSO treatment of C6 cells, although causing GSH depletion, has no effect on cell viability within 24 h. Only after longer periods was BSO cytotoxic to C6 cells (121). Overall, the study of GSH depletion in neurons may provide valuable insight in conditions such as Parkinson's disease, which is associated with decreased GSH in patients' brains...

Effects Of Atypical Antipsychotic Drugs On Mesotelencephalic Dopamine Systems

As with typical neuroleptic drugs, chronic administration of atypical antipsychotic drugs appears to affect dopaminergic systems in distinct ways. There have been reports of depolarization blockade in neurons within the ventral tegmental area, but not substantia nigra, after chronic clozapine 42 however, it appears that basal cortical, but not subcortical, dopamine efflux is increased after chronic clozapine.1617 Thus, after chronic clozapine, there may be a functional disconnection between impulse flow and release, possibly due to an emphasis on terminal-level-dependent regulation of transmitter release. In any regard, it appears that atypical antipsychotic drugs can facilitate cortical dopamine transmission after acute or chronic exposure, and this relative activation of cortical vs. subcortical dopamine release may subserve the superlative therapeutic effects in the absence of severe extrapyramidal side effects.

Pharmacological Interventions

Several attempts have been made in managing weight gain with adjunctive therapy utilizing non-FDA approved uses of several classes of medications, including oral hypoglycemics (metformin), anticonvulsants (topiramate), histamine H-2 receptor antagonists (nizatidine, famotidine), antiparkinsonian and antiviral agents (amantadine), antidepressants (reboxetine, fluoxetine, fluvoxamine), and others 74, 75 . However, few randomized clinical trials exist that test these agents among overweight or obese patients with schizophrenia. Approaches include the prevention of excessive weight gain when starting an antipsychotic, or the loss of weight already gained after receiving an antipsychotic for some time. Most of the studies enrolled small numbers of subjects and have mainly focused on ameliorating the weight gain observed with olanzapine. The randomized double-blind studies of these adjunctive agents 76-101 are summarized in table 4. Results are generally inconsistent. Many interventions as...

Electrochemical Techniques and Advances in Psychopharmacology

2Department of Psychiatry, Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA 3Department of Anatomy and Neurobiology, Morris K. Udall Parkinson's Disease Research Center of Excellence, Center for Microelectrode Technology, University of Kentucky Medical Center, Lexington, KY, USA

Enzymes Performing Amino Acid Conjugates

Kluwer Academic Plenum, New York Parkinson A, Ogilivie BW (2007) Biotransformation of xenobiotics. In Klaassen CD (ed) Casarett & Doull's toxicology the basic science of poisons, 7th edn. McGraw-Hill, New York Testa B, Kr mer SD (2010) The biochemistry of drug metabolism two

Extracellular Recording

In some instances it is desirable to record nerve cell activity without disturbing the cell membrane integrity. This can be achieved with extracellular recording. For example, this can be used to monitor the rate at which a cell fires action potentials. In the rat substantia nigra reticulata and ventral palladium, nicotine-induced increases in neuronal action potential firing rate were enhanced by alcohol (79). However, in the rat locus coeruleus, alcohol inhibited the excitatory effects of nicotine, kainate, and NMDA (80). Thus, the effects of ethanol on nicotinic receptors are not uniform in

Pathophysiology and Neuropathology

Pilocarpine-induced SE results in extensive brain damage similar to what has been observed after kainic acid.121381 When brains are examined 24 to 27 h after the pilocarpine injection, damage is found in the olfactory cortex, the amygdaloid complex, thalamus, neocortex, hippocampus, and substantia nigra.1281 Extreme damage, characterized by shrunken neuronal cell bodies with swollen edematous neu-ropil, is present in the anterior olfactory, pyriform, and entorhinal cortex. The basal amygdala and ventral hippocampus are particularly sensitive. In the dorsal hippocampus the majority of the damage occurs in CA3 and the dentate hilus while in the ventral hippocampus most of the damage occurs in CA3 and CA1. Neocortical cell loss occurs mostly in layer 2 and layer 3, with some cell loss in layer 5. The pars reticulata of the substantia nigra is also extensively damaged.13

Of Calcium Homeostasis In Acute

Parkinson's Disease Parkinson's disease (PD) is an age-related neurodegenerative condition that occurs in 1 of the population over 65 and is characterized by a progressive loss in the ability to initiate voluntary motor movement. PD involves a selective loss of dopaminergic neurons in an area of the midbrain called the substantia nigra (SN). This brain region makes connections with other brain areas such as the striatum, cortex, and thalamus and via this circuitry aids in the coordination of voluntary motor control. lipids. It can also eliminate both O2 and OH via nonenzymatic reactions. Although GSH is not the only antioxidant molecule reported to be altered in PD, it is the only one that shows a significant depletion in incidental Lewy body disorder of the basal ganglia, a closely related disease and arguably a precursor of PD (90,91). Decreases in GSH availability in the brain are believed to promote mitochondrial damage perhaps via increased levels of ROS (92-94). Reductions in...

Expression Trafficking and Targeting 41 Expression and Distribution

NR2A and NR2B are the most common NR2 subunits in the adult forebrain. NR2B is the most common also in the early postnatal forebrain and is replaced to some extent by NR2A during development. NR2C is abundant in adult cerebellar granule cells. NR2D is most common in early postnatal development in the diencephalon and brainstem. Receptor subunit abundance also may vary with neuron type within a region cortical parvalbumin-positive GABAergic interneurons at 21 days in vitro have a five-times-higher NR2A NR2B ratio than pyramidal neurons (54). Within neurons, NMDAR complexes are found at the synapse and in extrasynaptic locations, with the latter made up mainly of NR1 NR2B and NR1 NR2D types in fact, NR1 NR2D may never enter the synapse (55). In addition to diheteromeric NMDARs made up of two NR1 subunits and two NR2 subunits of one kind, triheteromeric NMDARs occur (5). Evidence for NMDARs containing two kinds of NR2 subunits has been shown for transfected cells and for a number of...

Behavioral Effects Induced by 5HT2C Receptors General Consideration

Regarding the interaction with DA transmission, the available data indicate that in most cases, both neutral antagonists (SB 242084, SB 243213) and inverse agonists (SB 206553) are facilitating the behavioral effects elicited by drugs of abuse or antiparkinsonian drugs. In one case, however, SB 206553 behaved differentially with respect to its regimen, facilitating locomotor hyperactivity induced by cocaine when administered at low doses (1 or 2 mg kg) and inhibiting it when administered at a higher dose (4 mg kg) (McCreary and Cunningham 1999). In the 6-hydroxy-dopamine rat model of Parkinson's disease, SB 206553 elicited by itself contralateral rotations when administered directly into the altered substantia nigra (Fox et al. 1998). These data suggest that SB 206553 differs sometimes from other antagonists in behavioral responses. This difference could account for its inverse agonism property (De Deurwaerdere et al. 2004) although a proper pharmacological characterization has never...

Gangliosides Definition

Sygen, a GM1 monosialoganglioside is one of about 60 plasma membrane glycosphingolipids thought to modulate cell signal transduction. It was developed for Parkinson's disease but was withdrawn due to an association with Guillain-Barre syndrome and a lack of benefit in Parkinson's disease. It was not available in the USA, except for compassionate use in spinal cord injury. Anti-Parkinson Drugs

Synthesis and Remarks

The existence of a constitutive activity in vitro is associated with the number of copies of the receptor expressed by the heterologous systems, and it is likely that this high expression for numerous GPCR is barely reached endogenously in vivo. There would be two other possibilities for a receptor to display a constitutive activity in vivo. First, the constitutive activity would be related to the very high capacity of the receptor to interact with G proteins. This property has been confirmed in vitro for native forms of 5-HT2C receptors (unedited form of the mRNA) (Berg et al. 1999 Niswender et al. 1999) but not for 5-HT2A receptors (Berg et al. 1999 Grotewiel and Sanders-Bush 1999) although they have been proposed to be constitutively active in conditioned behavioral responses (Harvey et al. 1999). In addition, the constitutive activity for 5-HT2C receptors has been associated with poorly edited forms for which the coupling efficiency and affinity for ligands are high compared with...

Clinical Applications Of

Geranylgeranylacetone (GGA), an acyclic polyisoprenoid developed in Japan, is widely used as an ulcer drug. In addition to a protective effect on gastric mucosal cells, GGA also has antiapoptotic effects against ischemia and reperfusion injury in hepa-tocytes and other cells. We have found that GGA induces TRX in hepatocytes and gastric mucosal cells and inhibits ethanol-induced cytotoxicity 71,72 GGA induces protein expression and secretion of TRX. GGA also induces TRX in PC12 cells and attenuates MPP-induced cytotoxicity, suggesting the use of GGA and or TRX in the clinical treatment of Parkinson's disease 73 . In addition to GGA, estrogen and prostaglandin E1 are also TRX inducers 74,75 . TRX induction by GGA and other TRX inducers may be beneficial for oxidative stress-induced disorders.

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Antipsychotic drugs vary according to their side-effect profiles regarding sedation, autonomic effects, and extrapyramidal motor symptoms. Sedation and autonomic effects are mediated, in part, by the muscarinic cholinergic and alpha adrenergic effects of the drugs. While the binding to D2 receptors predicts dosage and efficacy for antipsychotic drugs, it also predicts extrapyramidal motor symptoms (Seeman 1987). These include akathisia (or motor restlesness), dystonic postures, and parkinsonism (resting tremor, bradykinesia, and limb rigidity). Due to the functional relationship between dopamine and acetylcholine in the basal

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