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The Elements of Memory

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HT1C Receptors in Postmortem Human Brain Tissue

After characterizing the properties of the new site in animal (rat, pig) brain, we then went on with the characterization and localization of 5-HT1C receptors in postmortem human brain tissue. Taking advantage of the fact that Dr. Alphonse Probst, a pathologist at the University of Basel, shared a collaboration with Chema's group aimed to visualize and analyze neurotransmitter receptors in human tissue, we could use similar experimental procedures both in membranes and sections from a series of human brains, although confronting the specific limitations associated to the work with postmortem material. The 360-386 buildings connection worked again fairly well and by the end of 1985 the anatomical distribution and pharmacological profile of 5-HT1 and 5-HT2 receptors in the human brain were obtained, proving to be relatively similar to that reported in animals (choroid plexuses starring again), although species differences were evident - in fact, the marked species-dependent differences...

The Dopamine Hypothesis of Schizophrenia and Dopamine Receptors in the Human Brain

With the discovery of the antipsychotic dopamine receptor in vitro, it became possible to measure the densities and properties of these receptors directly not only in animal brain tissues but also in the postmortem human brain and, at a later time, in living humans by means of positron emission tomography. Many, but not all, of these findings directly or indirectly support the dopamine hypothesis of schizophrenia.

Ketone Body Metabolism in Human Brain

The availability of 13C-labeled metabolites for infusion allows 13C-MR spectroscopy to directly track the fate of ketones in human brain. As stated previously, 13C glucose studies in human brain have established that there is rapid entry of 13C molecules into the amino acid pools such as glutamate and glutamine, the amount of which reflects the fractional enrichment of infusate and plasma, the pool size of the amino acid, and the intervening metabolic fluxes. The tissue volume sampled in the 13C studies was typically between 50 and 125 cm3. However, because the white matter concentrations of amino acids such as glutamate and glutamine are approximately half the concentration of gray matter, and because the sampled tissue regions can be biased toward a greater gray matter fraction, with adequate modeling, such large tissue voxels can still be insightful. This is particularly true for steady state studies, in which the total labeling can be attributed to known pool sizes, and concerns...

Neuroanatomy Of The Acetylcholine System

The distribution of ACh-containing axons in the cerebral cortex is heterogeneous, with paralimbic areas having the greatest density of ACh-containing axons. The sensory and association regions of neocortex are less densely innervated by cholinergic axons than are the paralimbic areas. For example, in human brain, the density of cholinergic axons is lowest in the primary visual cortex moderate in association areas, including parts of the prefrontal (see Figure 4-3) and parietal cortices and highest in the paralimbic entorhinal and cingulate cortices (Mesulam et al. 1992). The density of cholinergic axons also differs within a cortical region. In monkey prefrontal cortex, there is a rostral to caudal increase in the density of ACh-containing axons, so that area 10 at the frontal pole has a lower density of cholinergic axons than does area 9, which is less densely innervated than the more caudal area 8B. Furthermore, the more caudal premotor (area 6) and motor (area 4) cortices have the...

Neuroanatomy Of The Dopamine System

Projections of dopamine-, norepinephrine-, serotonin-, and acetylcholine-containing neurons in the human brain. The cerebral cortex is another major projection site of DA neurons, and this projection arises from cells within the substantia nigra dorsalis, ventral tegmental area, and retrorubral area (Lewis et al. 1988b Williams and Goldman-Rakic 1998). Although early studies suggested that DA projections to the neocortex in the primate were restricted to frontal and temporal regions, it has since been demonstrated that essentially all cortical regions in the primate are innervated by DA axons, although the density of innervation differs substantially across regions (Gaspar et al. 1989 Lewis et al. 1987, 2001 Williams and Goldman-Rakic 1993). In both nonhuman primate and human brains, the motor and premotor cortices, as well as certain areas of the prefrontal (Figure 4-3) and posterior parietal cortices, contain a high density of DA axons. In these areas, DA axons are...

Imaging Of The Brain In Neuropathic Pain

Recent advances in human brain imaging techniques offer an exciting opportunity to examine brain processes in experimental and clinical pain conditions. This has allowed insights into neural correlates of pain and led to a much greater understanding of the pain matrix,191,192 which includes brain structures, such as the anterior cingulate cortex (ACC), insula, frontal cortices, S1, second somatosensory cortex (S2), and amygdala.193

HT1C Autoradiographic Characterization

Angel was dealing for a long time with the challenges and possibilities of brain anatomy across species. Studies were first designed to identify brain areas specially enriched in the different subtypes of 5-HT1 receptors proposed in order to reinforce the singularity of 5-HT1C sites as a separate entity from the others. At that time, there was already quite some evidence that 5-HT1 binding was divided into 5-HT1A and 5-HT1B (Pedigo et al. 1981) and 8-OH-DPAT had just been reported as a 5-HT selective agonist (Gozlan et al. 1983 Hjorth et al. 1982 Middlemiss and Fozard 1983).

Evaluation of Seizures and Epilepsy

The EEG is our primary tool for recording the electrical activity of the human brain. Small disk electrodes are attached to the scalp at specified locations. When sufficiently amplified, voltage changes generated in neocortical neurons are recorded on the EEG as waveforms of various frequency, amplitude, and morphology. EEG patterns vary according to the patient's age, state of alertness, and genetic predisposition. The EEG may also record pathologic waveforms such spikes and sharp waves (representing the summated activity of many neurons firing synchronously) or focal slow waves (reflecting localized brain dysfunction). These abnormalities may be recorded in a given region (focal) or over the entire cortical surface (generalized). Because, however, the EEG records activity from near the brain's surface, mainly from neocortex, electrical activity emanating deep within the brain, e.g., brainstem, thalamus, and temporal lobe structures such as hippocampus, may not be recorded reliably...

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ACh is necessary for control of skeletal muscle in verterbrates, acting as the neurotransmitter at the neuromuscular junction. It is also involved in transmission in the autonomic nervous system (see below, under Neuroanatomy). Central ACh is produced in two general areas in the brain incuding the basal forebrain (medial septal nuclei, diagonal band

Culture and Manipulation of Neural Stem Cells

A major obstacle in the treatment ofbrain tumors is overcoming the difficulty ofdelivering therapeutic agents to specific regions ofthe human brain. Molecules that might otherwise be effective may be unable to cross the blood-brain barrier or cross in inadequate amounts. However, NSCs are able

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

The pharmacological profile for 5-HT2C receptors is very similar for human, pig and rat (Hoyer et al. 1985, 1986 Pazos et al. 1984b, 1987) both radioligand binding and autoradiographic procedures in frontal cortex, hippocampus, and choroid plexus of these species using 3H mesulergine. The distribution of 5-HT2C receptor binding sites in the human brain is somewhat different from that found in the rat brain (Pazos and Palacios 1985 Hoyer et al. 1986). In the rat hippocampus, 5-HT2C receptor binding sites are located in the stratum lacunosum molecular, whereas in the human hippocampus the pyramidal layer is enriched in these receptors. 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...

Matrix Metalloproteinases

Several studies have attempted to elucidate the expression pattern of MMPs in the human brain. In autopsied brain samples from patients without any demyelinating disease of the CNS, MMP-1, -2, -3 and -9 could be localized to microglia and astrocytes. An increase in the expression of these MMPs was noticeable in samples from MS patients. In addition, perivascular macrophages were found to stain positive for MMP-9. The cytokines known to induce MMP-9 expression are also detectable within active MS lesions, both in perivascular cells and in activated microglia.81,82

Materials and Methods

Sanai N, Tramontin A, Quinones-Hinojosa A et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 2004 427(6976) 740-4. 20. Palmer T, Schwartz P, Taupin P et al. Cell culture. Progenitor cells from human brain after death. Nature 2001 411(6833) 42-3.

Central excitatory systems

The long-term increase in pain sensitivity frequently seen following injury or peripheral nerve damage is thought to be due to both alterations in transmission within the spinal cord and to changes in descending controls that run back to the spinal cord from the brainstem. Within this circuit, nocic-eptive information is also relayed to higher centers in the brain via projection neurones. The neuroanatomy of these ascending pain pathways is highly complex, and supraspinal contacts include centers involved with the sensory-discriminative aspects of pain such as the intensity, location and duration of the stimulus as well as centers involved in the affective-cognitive aspects including anxiety, emotion and memory 61 . Importantly, these are the same areas of the brain that modulate descending serotonergic and noradren-ergic inputs from the brainstem that regulate nocic-eptive processing at spinal levels. Thus, a network of spinal and brain circuits can change spinal sensitivity

Interconnections between neurons

The interconnections or communication among neurons in humans is very extensive. Imagine the complexity of the electrical activity that may occur among 100 billion neurons in the human brain where each of these neurons provides input to and receives input from hundreds of other neurons. It is the diversity of these interconnections that accounts for the uniqueness of many abstract neurological phenomena in individuals such as intellect, personality, and memory. The two types of interconnections are

Macromolecular Drug Delivery 2421 Intraventricular Route

In adult human brain, the total CSF volume amounts to 100-140 ml and the production rate is 21 ml h-1 63 . Accordingly, the entire cerebrospinal volume is exchanged regularly 4-5 times per day. This rapid drainage of CSF into peripheral blood leads to relatively high drug concentrations in the peripheral circulation. For instance, the concentration of methotrexate in peripheral blood reaches 1 of the ventricular CSF concentration following intrathecal administration of the drug 64 . In Rhesus monkeys, parenchymal concentrations of methotrexate of 1 of the intraventricular concentration have been measured at a distance of 2 mm from the ependymal surface 65 . Therefore, the concentration of methotrexate in the blood is actually higher than at tissue regions beyond

Intraparenchymal Route

Restricted diffusion also limits tissue distribution after intraparenchymal drug administration, as shown in Figure 2.7c and d. Distribution has been measured in the rat brain after implantation of polymer discs containing NGF 66 . Drug concentrations decreased to less than 10 of the values measured on the disc surface within a distance of 2-3 mm, even after prolonged periods of several days. Therefore, applying this approach in the larger human brain would require the stereotaxic placement of multiple intraparenchymal depots, as has been evaluated in rat brain 67 , on a repetitive schedule.

Why Does Myelin Regeneration Fail In Multiple Sclerosis

In different experimental models of focal demyelina-tion, it has been shown that the adult rodent CNS has endogenous potential for regenerating oligoden-drocytes and myelin. Attempts to regenerate myelin can also be recognized pathologically in brains of multiple sclerosis patients by the existence of shadow plaques, which are partially remyelinated lesions.21-23 However, as disease advances, there is subsequent failure of remyelination. Data from experimental models of demyelination and from human brain tissue suggest that several factors may play a role in limiting myelin regeneration in the adult brain and its subsequent failure. In experimental focal demyelination it has been shown that only a subpopulation of local progenitor cells react to injury and generate new oligodendrocytes and myelin.17 Although progenitor cells were demonstrable in acute and chronic multiple sclerosis (MS) lesions, they did not exhibit reactive increases in cell number as compared to normal white...

Overview and Pathogenesis of Alzheimers Disease

Alzheimer's disease is a devastating illness. It occurs mainly in the elderly population. Once afflicted, Alzheimer's disease produces progressive and unrelenting damage to the human brain. The average lifespan after being diagnosed with this illness is about 8-10 years 1 . Patients steadily lose cognitive functions including memory, executive functioning, and the ability to care for themselves. In addition, behavioral symptoms of agitation, depression, and psychosis are often co-morbid with Alzheimer's disease. This devastating illness affects not only the patients but also the families and anyone that provides care for them. In the United States, the staggering financial cost of the disease accounts for nearly 100 billion per year in medical and custodial expenses, with the average patient requiring about 27000 per year for medical and nursing care. Furthermore, 80 of caregivers of patients with Alzheimer's disease report stress, and about 50 report depression 2 .

In Vivo Voltammetry

Voltammograms obtained with standard methods contain waves composed of oxidation currents from several compounds (composite peaks), and therefore they are considered ''of little or no analytical use'' 43 . Different electrode materials, electrode surface modifications, applied potential procedures, and mathematical models for data analysis have been tried in the pursuit of improved separation of the small neurotransmitter peaks from the large AA and metabolite peaks. Despite difficulties, measurement of specific compounds in the ECF has proved feasible, and IVV has generated a large volume of information on the release and metabolism of biogenic amines in human brain. Moreover, the search for better chemicals, as well as temporal and spacial resolution, has contributed to the development of the field of voltammetry and generated a variety of new applications. The aim of this section is to briefly describe IVV and its application for measuring redox phenomena in the ECF....

RNA Editing of the 5HT2C Receptor

Have base-pairing properties similar to that of guanosines, they are recognized and translated as guanosine by the ribosomes. RNA transcripts encoding the human 5-HT2C receptor undergo adenosine-inosine (A-I) editing events at five positions, A, B, C, D, and E (Fig. 5.1), altering the amino acid sequence in the putative second intracellular loop of the protein and resulting in at least 21 discrete mRNA species encoding 14 different editing variants of the 5-HT2C receptor (Burns et al. 1997 Niswender et al. 1998). In human brain, the genomic (unedited) receptor expresses amino acids isoleucine, asparagine, and isoleucine (INI) at positions 156, 158, and 160, respectively (in the sequence IRNPI in the intracellular loop 2), whereas conver-

Choosing the Surgical Procedure

On the other hand, multifocal CNS disorders, such as amyotrophic lateral sclerosis (ALS), MS, or Alzheimer's disease are characterized by global inflammation and demyelination throughout the entire nervous system and are thus perhaps best treated by delivering NSCs intravenously or directly into the cerebrospinal fluid circulation to better facilitate distal cell delivery.8 NSCs travel universally throughout the vascular system and reach multiple inflamed areas in the brain and spinal cord by specific homing in on target cues. Evidence suggests that aNSCs express a variety of inflammatory molecules such as adhesion molecules, chemokines, cytokines and chemokine receptors8,73 which organize the migration and differentiation of precursors during development.73-75 These molecular signals support aNSC interactions with endothelial and ependymal cells surrounding inflamed brain tissues74,76,77 and create a chemoat-traction gradient78,79 that is cited as the main mechanism through which...

Clinical Relevance of Kindling

A common criticism of kindling is that there is little documented evidence that humans kindle. For obvious reasons this concern is difficult to address. Although there exist at least two reports of kindled epileptogenesis occurring in the human brain following repeated direct stimulation with implanted intracranial elec-trodes,9697 and several instances of recurrent spontaneous convulsions in schizophrenic patients receiving repeated electroconvulsive therapy,54 a definitive answer to this criticism is impossible. A question that can be addressed, however, is whether the phenomenon of clinical epilepsy has kindling-like properties. A second clinical phenomenon that many have postulated to reflect kindling of the human brain is posttraumatic epilepsy.6,54,86,98 Patients with this condition often present with CPS, months to years after a serious brain insult. During the intervening silent period between the initial trauma and the appearance of clinical seizures, injured brain tissue, or...

ThE ORphAn Receptor Gpr55

GPR55 is a member of the purine receptor subset of the GPCR superfamily, having highest identity to GPR35 (37 identity), P2Y5 (30 ), GPR92 (30 ), and GPR23 (29 ) (Baker et al., 2006). Three of these related receptors are reportedly activated by lysophosphatidic acid (P2Y5, GPR92, and GPR23 Lee et al., 2006 Noguchi et al., 2003 Pasternack et al., 2008). GPR35 is weakly activated by kynurenic acid (Wang et al., 2006), but conceivably may also be activated by as yet unidentified endogenous lipid mediators. GPR55 mRNA was detected by Northern blotting in human brain (in the caudate nucleus and putamen, but not in the hippocampus, thalamus, and mid-brain). In situ hybridization in the rat brain showed expression in the hippocampus, parts of the thalamus and midbrain. In peripheral tissues, expression was found in the spleen and intestine and there was also mRNA in fetal tissues (Sawzdargo et al., 1999).

Historical Perspective

It took several decades to agree that new neurons are generated in adult brain but less time to establish that they are functionally integrated in two discrete regions the olfactory bulb (OB) and the hippocampus (Ming and Song 2005 Lledo et al. 2006 Zhao et al. 2008). While our current knowledge on adult neurogenesis in mammals is mainly based on rodent studies, recent in vivo data have confirmed the occurrence of neural stem cells in the human brain (Manganas et al. 2007), already detected in postmortem tissues (Eriksson et al. 1998). Originally described by Altman (Altman 1969) using 3H thymidine autoradiography, the presence of new neural cells in adult brain was rediscovered by Gould et al. in the early 1990s (Gould et al. 1992 Cameron et al. 1993) in studies based on the administration of 5-bromo-2'-deoxyuridine (BrdU), a thymidine analogue taken up by cells synthesizing DNA in preparation for division. BrdU-labeled neurons are visualized using a method, immunocytochemistry,...

Neurons Can Also Carboxylate Pyruvate And Are Therefore Not Completely Dependent On Glutamine As A Precursor For

In the following we will therefore assume that 50-80 of brain glutamine is formed from transmitter Glu. In the rat and human brain the level of glutamine is 60 nmol mg protein, of which 50-80 , i.e. 30-50 nmol mg protein, may be formed from transmitter Glu. This value corresponds to the transmitter Glu pool size (20-30 of a brain level of 100-120 nmol Glu mg protein). The flux of transmitter Glu to astrocytic glutamine would then be 20-30 of the whole brain turnover rate for Glu (16-20 nmol mg protein-1 min '), i.e. 3-6 nmol mg protein' min-1 this value is similar to the value of 2.1 nmol mg protein-1 min-1 obtained in anesthetized rats (Sibson et al., 1997). Because some of the transmitter Glu may be metabolized via non-glutamine pathways, e.g. to lactate (Hassel and Sonnewald, 1995a McKenna et al., 1996), the total flux of Glu to astrocytes may be somewhat higher.

Activin A and Neuroprotection Findings from Animal Studies

The development of an analytical assay in the last few years has made it possible to measure activin A concentrations after brain injury in humans. Until now, activin A measurement after human brain injury was generally limited to hypoxic ischemic encephalopathy (HIE) in the perinatal period. The findings that the fetus is the main source of activin A in the umbilical cord blood during pregnancy 45 and that increased umbilical cord activin A levels are an indirect marker of impaired blood flow in the fetal circulation 46 may provide an index of fetal hypoxia in preterm newborn 47 . These observations, together with in vitro evidence showed that induction of activin A occurs early after brain injury, have prompted investigations as to whether activin A could provide additional information to physicians and indicate occurrence of perinatal brain injuries at a stage when diagnostic procedures are of limited benefit. This approach could thus permit implementation of earlier therapeutic...

The Pathophysiology of PD may Include Oxidative stress Inflammation andor Excitotoxicity

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 can rapidly oxidize 111 , and in so doing can cause relatively specific lesions of DA neurons when injected into the striatum ( 112 see reviews 113,114,115 ).

The Principle of Pain and Its Physiology

Chinese theory indicates that pain is frequently associated with stagnation or obstruction of Qi, and the application of acupuncture stimulation unblocks this obstruction and stagnation resulting in the resolution of this pain (Liu and Akira 1994). The Western physiology of pain perception and modulation describes a multilevel system that is activated once an injury occurs under normal circumstances. The peripheral activation leads to a series of events processing toward the central nervous system. This leads to a sequence ofevents including signal processing along neural pathways, immunologic, hormonal release, and psychobehavioral responses (Wang et al. 2008). Pain perception and inhibition accept a dynamic, malleable, and complex set of interacting neurons with gene regulation and expression producing a variety of neuropeptides and cytokines at both the peripheral and the central nervous systems (Besson 1999, Melzack and Wall 1965, Bolay and Moskowitz 2002). The recognition of the...

The 5HT2 Receptor Family

5-HT2 receptors form a closely related subgroup of G-protein-coupled receptors, are functionally linked to the phosphatidylinositol hydrolysis pathway, and are currently classified as 5-HT2A, 5-HT2B, and 5-HT2C subtypes, based on their close structural homology and pharmacology (Hoyer et al. 1994 Barnes and Sharp 1999 Boess and Martin 1994). There is a high sequence homology (> 80 in the transmembrane regions) between the mouse, rat, and human 5-HT2C receptors (Barnes and Sharp 1999), and it is not surprising that many compounds bind with high affinity to all three receptor subtypes. 5-HT2C receptors are widely distributed throughout the brain and have been proposed as the main mediators of the different actions of 5-HT in the CNS (Hoyer et al. 1994 Barnes and Sharp 1999 Boess and Martin 1994). High levels of 5-HT2C mRNA or protein expression have been found in the choroid plexus, the frontal cortex, in limbic structures such as hippocampus, septum, and hypothalamus and in the...

Dopaminemediated Learning Aging and pd

In aging, the deficiency of dopamine in the prefrontal cortex results in the deficit in working memory, whereas, in acute stress, excessive dopamine neurotransmission leads to impairment in working memory. These impairments can be attenuated by D1 receptor agonist and antagonist treatment, respectively 93-94 . Age-related loss of dopamine synthesis has been reported in the striatum as well as in the extrastriatal regions except midbrain in the postmortem brain 95 . Age-related loss of D2 and D3 receptors has been observed in the striatal and several extrastriatal regions in normal human brain 96 . Age-related decline in brain performance, including learning, is due to deterioration of synaptic contact and changes in neurotransmitters neuromodulators concentrations 93-94,97 .

The Role Of Nitric Oxide In Ischemic Brain Injury

NO is a mediator involved in a wide variety of physiological and pathological processes. NO is synthesized by the enzyme NO synthase (NOS) by the oxidation of the guanidino nitrogen of L-arginine.55 Immediately after induction of ischemia, the vasodilator effect of NO, produced mainly by endothelial nitric oxide synthase (eNOS), is believed to protect the brain by limiting the degree of flow reduction produced by the arterial occlusion.56 However, following ischemia, NO produced by neuronal NOS (nNOS) and, later, by inducible NOS (iNOS), may contribute to the evolution of brain injury.57 Expression of iNOS occurs in the setting of such inflammatory reactions. Following permanent or transient MCAO in rodents, iNOS mRNA, protein and enzymatic activity are expressed in the post-ischemic brain.58,59 The expression peaks 12-48 h after ischemia and occurs in inflammatory cells infiltrating the injured brain and in cerebral blood vessels.60 iNOS expression was also found in neutrophils and...

Factors to Be Addressed in Psychotherapy

Little can be done to facilitate rehabilitation and restoration of functioning unless comorbid mood disorders are addressed and treated. Given that the neu-rophysiology and neuroanatomy of pain processing pathways overlap with those of affective processing and experience, pain perception and mood states (e.g., depression and anxiety) have mutually reciprocal relationships. Thus, affective states may influence pain perception, pain reporting, and pain-related behaviors. For example, the severity of a patient's depressive symptoms has been shown to predict the number and severity of pain complaints (Hawley and Wolfe 1988). Depression is a significant predictor of average daily pain (Affleck et al. 1991).

Genetic Studies Knockout or Other Studies

Loss of spontaneous and evoked EPSCs in immature granule cells and exhibit problems in motor coordination (248). Knockout of NR2D produces mice with lower sensitivity to stress and altered monoaminergic neuronal function (249), and overexpression of NR2D produces prominent impairment of NMDA-dependent LTP (250). The most essential subunits must be NR1 and NR2B, based on transgenic mouse studies (reviewed in refs. 6 and 251). Knockout of NR1 leads to death shortly after birth. Although neuroanatomy is generally normal, some of the sensory input connections are disturbed. Because NR1 appears to be required for all functional NMDARs, NMDARs must be essential for nervous system function after birth, although they are not required for the general pattern of neural development. Mice with only a partial KO of NR1, expressing about 5 of normal levels, survive to adulthood but display behavioral abnormalities resembling schizophrenia, supporting earlier studies showing that...

Brain Imaging In Psychopharmacology Introduction

Functional brain imaging refers to a class of techniques that noninvasively measure correlates of neural activity. Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are the two technologies most commonly used today to study the human brain in action. The explosion of information about human brain function occurring in the past decade has resulted in large part from these two techniques. As will be described in this chapter, PET imaging has made considerable contributions to our understanding of the mechanisms of drug action, mostly through application of radiopharmaceutical labeling of neurotransmitter receptors. fMRI, on the other hand, has gained rapid acceptance because of the widespread availability of magnetic resonance imaging (MRI) scanners, the lack of radioactive exposure, and the better image resolution offered. The advent of neuroimaging techniques for probing in vivo human brain function undoubtedly represents a major milestone in the...

Mr Imaging And Spectroscopy

In 1H-MR spectroscopy, the compounds NAA, creatine, choline, lactate, glutamate, glutamine, acetone, y-aminobutyric acid (GABA), myoinositol (mI), glucose, and P-hydroxybutyrate (BHB) are all relatively well detected. Compounds present in lower concentrations, approx 1mM, e.g., lactate, GABA, BHB, represent a greater challenge for measurement than those present in more abundant concentrations of approx 5-12mM, e.g., NAA, creatine (Cr), and thus have required more specialized detection approaches. 31P-MR spectroscopy can evaluate high-energy phosphates (ATP, phospho-creatine), as specific assessments of the bioenergetic state. 13C-MR spectroscopy, although of considerably less sensitivity than 1H or 31P imaging, can allow a dynamic assessment of neurotransmission and amino acid turnover in the human brain.

Ketosis And The Ketogenic Diet In Epilepsy

Fig. 2. (A) Spectrum of 13C -labeled metabolites obtained using 13C -2,4-P-hydroxybutyrate infusions from in vivo human brain. The spectrum is acquired starting 60 min into a bolus-plateau infusion protocol and acquired during the 60- to 120-min time period. (B) Comparison of spectra obtained using three different 13C-labeled metabolites to demonstrate the pattern of labeling. 13C BHB labels broadly similar to that seen with glucose, consistent with its use by the large neuronal pool detailed modeling of the glutamate and glutamine pools suggest that it is favored by the neuronal pool, whereas acetate is favored by the glial pool. Fig. 2. (A) Spectrum of 13C -labeled metabolites obtained using 13C -2,4-P-hydroxybutyrate infusions from in vivo human brain. The spectrum is acquired starting 60 min into a bolus-plateau infusion protocol and acquired during the 60- to 120-min time period. (B) Comparison of spectra obtained using three different 13C-labeled metabolites to demonstrate the...

Anestheticampakainate Receptor Interactions In Vitro Studies

However, enflurane (1.8 mM) inhibited both AMPA- and kainate-stimulated currents in Xenopus oocytes expressing mouse brain mRNA by approximately 30 .35 As noted above, this study reported a similar magnitude of inhibition for NMDA currents in these oocytes. The percent inhibition was not different in the presence of maximal and minimal concentrations of AMPA or kainate, suggesting that enflurane does not compete for these agonist binding sites. This site of action also was ruled out for enflurane at NMDA receptors. Of the glutamate agonists, only kainate produced measurable currents in oocytes expressing post-mortem human brain mRNA. Human kainate channels were inhibited by enflurane to a similar degree as mouse kainate responses. Thus, no species or glutamate agonist differences were observed with respect to enflurane action. However, the agonists AMPA and kainate can both stimulate AMPA subtypes of glutamate receptors. It is only this subtype that would be activated in oocytes...

Brain Glucose Metabolism A Synopsis

The energy requirements of the human brain are enormous. Cerebral oxygen consumption is 35 mL min kg or approx 50 mL min in the adult brain. The rate of whole-body O2 consumption is 250 mL min, indicating that approx 20 of oxygen utilization is directed toward the needs of the brain, which occupies only 2 of body weight. Virtually no oxygen is stored in the brain, implying that to maintain the integrity of this vital organ, cerebral blood flow (approx 800 mL min), which constitutes about 15 of cardiac output, must proceed in an uninterrupted manner. If flow is completely shut down, a state of unconsciousness would ensue within 10 s.

Supraspinal Distribution Of The Delta Opioid Receptor

Once the genomic sequences for the & -opioid receptors have been identified, it became possible to engineer mRNA probes corresponding to the genetic structure of the genes in order to allow for in situ hybridization techniques to identify the distribution of neurons that actually express the receptors 58 . Moreover, RT-PCR could also be employed to determine the general distribution of the & -opioid receptors throughout the nervous system. For example, RT-PCR and Northern blot analysis performed in human brain sections showed a high concentration of & -opioid receptors in the cortical and hippocampal sections and the caudate nucleus and the nucleus accumbens and little or no signal in the medullary and mesencephalic sections 59 . These findings were consistent with the proposed existence of an enkephalinergic 63 . Recent receptor autoradiography and in situ hybridization studies have clearly demonstrated the presence of 5-opioid receptors or of 5-opioid receptor mRNA...

Dopamine Transporters DATs

High binding of DAT radiotracers has been found in the caudate and putamen, regions known to have a high density of the DAT 48 . The striatum is thus a suitable region for determination of changes of DAT binding as a result of drug interactions. Phenyltropane is one of the chemical scaffolds that has been applied for the development of selective tracers for DAT. The cocaine analogues, such as P-CFT P-CIT and RTI-121 (3P-(4-iodophenyl)tropane-2P-carboxylic acid isopropyl ester) have been extensively used as markers of DAT in animals or in the human brain (Fig. 6). In vivo studies with both SPECT and PET have been performed in monkeys and humans, particularly using P-

The Pathology Of Alzheimers Disease

To and sometimes indistinguishable from those that occur in AD have been described in several less common neurodegenerative diseases, usually without accompanying Ap deposits and neuritic plaques. Conversely, Ap deposits can be seen in aged 'normal' human brain in the virtual absence of tangles. Infrequently, AD cases are seen which are 'tangle-poor', i.e. with very few NFTs despite abundant Ap plaques.21

D2Like Dopamine Receptor Genes 221 D2 Dopamine Receptor Genes 2211 Gene Structure and Organization

The polymerase chain reaction amplification of mRNA from rat brain revealed the existence of two shorter isoforms of the D3 dopamine receptor in addition to the D3 dopamine receptor itself 59 . The isoforms were suggested to result from different processes of alternative splicing. One form was produced by splicing of an exon whose absence deletes the third transmembrane domain, resulting in a protein (termed D3(TM3-del)) having no dopaminergic ligand binding activity. The second isoform resulted from splicing at a receptor site that coded for half the second extracellular loop and part of the fifth transmembrane domain (referred to as D3(O2-del)). Other research groups have also demonstrated splice variants of the D3 dopamine receptor in the rat and human brain 60-62 , but none of the truncated proteins encoded by these variants has dopamine receptor activity. However, the alternatively spliced short isoform of the mouse D3 dopamine receptor that lacks 63 nucleotides in the third...

Nicotinic Acetylcholine Receptor Subtypes

NAChRs belong to a superfamiliy of ligand-gated ion channels characterized by a conserved sequence in the N-terminal domain flanked by linked cysteines that also includes 5-HT3, GABA and glycine receptors. These highly conserved, integral membrane proteins are pentameric structures, composed of a and b subunits. To date, nine a (2-7, 9-10) and three b (2, 3, and 4) subunits have been identified in the CNS. nAChRs may consist of five identical subunits (homomeric) or two or more different sub-units (heteromeric). The a7 subunit forms homomeric receptors, a major component of the nAChRs in the CNS. Heteromeric receptors formed by the a4 and b2 subtypes are the principal receptor types in the mammalian brain. Some subunit combinations are more widely expressed in the CNS than others, while some are restricted to well-defined neuronal pathways. For example, the a6-contain-ing receptor, which predominantly results from coassem-bly with a4 and b2 subunits, is preferentially expressed in the...

In vitro dissolution of amyloid

Unlike the hydrophobic mechanism that forms AP fibrils, metal-induced AP precipitation proceeds through two pathways- 1. reversible, ionically-mediated oligomerization, 2. Cu-mediated AP oxidation and cross-linking. High affinity chelators both inhibit and reverse AP precipitation induced by metal ions, and dissolve deposits from post-mortem human brain tissue 143,183 (Table 2). AP also recruits the contaminating metal ions in ordinary laboratory buffers to form the micronuclei that seed the precipitation of peptide solutions into fibrils. Therefore, even the formation of fibrils in the

Introduction to Molecular and Functional Imaging

Using PET as a tool for molecular and functional imaging, we can measure cerebral energy (glucose) consumption by injecting 18F fluorodeoxyglucose ( 18F FDG). Increased regional brain activity may result in increased demands for glucose and oxygen, inducing dilation of brain capillaries. This can be accompanied by an increase in regional cerebral perfusion, which can be measured using PET and radiolabeled water ( 15O H2O), and other methods such as functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS). Nowadays, PET is more often used for measuring regional brain glucose consumption and for evaluating neurotransmission function. In the human brain, neurotransmitters can exert their actions even in very small amounts. It is not easy to visualize the actions of neurotransmitters in the living human brain externally without using a highly sensitive technique such as PET. In addition, PET enables the quantification of interactions between neurotransmitters and...

Factors Impacting Ocular Transporters And Metabolizing Enzymes

However, it has been argued that due to the theoretical route of ophthalmic timolol into the systemic circulation via the nasolacrimal duct, with absorption through the nasal mucosa with venous delivery to the heart, the impact of a first-pass hepatic effect should be minimal (59). Thus, an alternative explanation may be related to the impact of ocular tissue CYP2D6-mediated metabolism. In the past, it has been assumed that timolol is unlikely to undergo ocular metabolism that achieves clinical significance in the eye or body. This assumption is likely based on early metabolic studies conducted in rabbits that demonstrated minimal metabolism in ocular tissues (60). However, these studies were conducted 20 years ago and significant advancements have been made in the methodology and technology used to study extrahepatic metabolism. In fact, we have observed CYP2D expression and activity in rabbit ocular tissues (31). Potentially, polymorphic CYP2D expressed in...

Receptor Proteins And Genes In Leukocytes

Exon coding regions while the kappa receptor contains an additional exon 5' of the translational start site 26 . A cDNA clone isolated from a PHA (phy-tohemagglutinin)-activated human lymphocyte population which encodes the opioid orphan receptor has complete homology to the clone isolated from human brain, but divergence at the 5' untranslated region indicates tissue specificity of gene expression. Upon lymphocyte activation with PHA, a 10-fold induction of the orphan message was observed 27 . Distribution of the opioid receptor-like 1 (ORL-1) transcript has been observed in normal circulating human T-, B-, and monocytic cell lines by RT-PCR and RNAse Protection assay. These transcripts lack a 15-nucleotide stretch between exons 1 and 2 comprising the first intracellular loop but otherwise show similar distribution to the brain transcripts of the cortical areas, striatum, thalamus, and hypothalamus 28 . Low levels of delta opioid receptor (DOR) are consistently detected by RT-PCR...

Subtype Selective Antagonists

An alternative approach to the problem of preventing receptor overactivation while permitting enough normal glutamatergic function to avoid unacceptable side effects has been the development of NMDA receptor subunit-selective compounds. In the adult rodent and human brain the predominant NR2 subunits in the forebrain are NR2A and NR2B, with NR2C expressed largely in the cerebellum and various select nuclei, and NR2D expression confined to the diencephalon and midbrain (30,32,34,125). NMDA recep

Gene Based Approaches to Therapy

Trophic response to NGF in the human brain. A,B) Nissl stain of autologous, NGF-secreting cell implant in brain of individual with Alzheimer disease 5 weeks after treatment. Graft (g) adjacent to nucleus basalis of Meynert (nbm arrows). Inset, robust mRNA encoding NGF by in situ hybridization within graft. Scale bar in a, 247 m in b, 24 m. Note proximity of graft to nbm, seen in similar perspective in c at higher magnification. C,D) Immunocytochemistry for cholinergic neurons (p75) shows graft implant on left (g) and adjacent neurons of nbm (arrows). Higher magnification (D) shows dense penetration of cholinergic axons into graft. Scale bar in c, 82 m in d, 11 m. Reprinted with permission from Tuszynski MH et al. Nat Med. 2005 11(5) 551-555.110 Figure 5. Trophic response to NGF in the human brain. A,B) Nissl stain of autologous, NGF-secreting cell implant in brain of individual with Alzheimer disease 5 weeks after treatment. Graft (g) adjacent to nucleus basalis of Meynert...

Antioxidant Vitamins

Monoamine oxidase B (MAO-B) is an enzyme that induces monoamine oxidation in the human brain. MAO-B activity is increased in Alzheimer's disease, which is thought to contribute to the neurotransmission defects associated with the disease (104-109). L-Deprenyl (selegiline) is a selective irreversible inhibitor of MAO-B (at low doses of up to 10 mg daily) (110), which has been reported to have some beneficial effects in AD. Whether selegiline is efficient in the management of cognitive and behavioral symptoms of AD is still a question of controversy. Several studies have provided conflicting results as to the effects on improvement in symptomatology. A detailed discussion of selegiline in AD is beyond the scope

Expression of Chemokine Receptors in Cells Intrinsic to the Central Nervous System

Increasing evidence highlights the prominence of chemokines in a variety of physiologic and pathologic processes in the CNS. In particular, chemokines have been shown to be critical determinants in the positioning of cellular population in the development of CNS inflammation due to autoimmune reactions or infectious diseases (2,15). Several lines of evidence indicate that all resident cells of the CNS express functional chemokine receptors in the intact human brain and in the CNS of rodent and macaques as experimental models. Astrocytes and microglia express most of the chemokine receptors including CCR3 (16-18), CCR5 (17), CXCR3 (19-21), and CXCR4 (18,22,23). Functional expression of CCR2 by fetal human astrocytes (24) and by reactive microglia in multiple sclerosis (MS) lesions (25) has been documented. Confined exclusively to microglia in vivo is the expression of CX3CR1 (26,27). Neurons exhibit expression of CCR1 (28), CXCR1 (29), CXCR2 (29), and CXCR4. Neuronal CCR1 expression,...

Application of DAT Imaging

Transaxial, SPECT images of human brain at 3 h post-i.v. injection of 20 mCi of 99mTc TRODAT-1 for normal and parkinsonian subject, respectively. In the normal subject, a high accumulation of 99mTc TRODAT-1 was observed in caudate and putamen, where dopamine transporters are concentrated, whereas the parkinsonian patient (right) displayed a dramatic decreased uptake in this region of the brain. A comparable post-mortem brain section of a normal human is displayed on the left. (See color insert.) Figure 15.3. Transaxial, SPECT images of human brain at 3 h post-i.v. injection of 20 mCi of 99mTc TRODAT-1 for normal and parkinsonian subject, respectively. In the normal subject, a high accumulation of 99mTc TRODAT-1 was observed in caudate and putamen, where dopamine transporters are concentrated, whereas the parkinsonian patient (right) displayed a dramatic decreased uptake in this region of the brain. A comparable post-mortem brain section of a normal human is displayed on...

Serotonin Transporter Sert Imaging Agents

Of this system are related to depressive illness and other psychiatric disorders and therefore potentially can benefit millions of patients who are being treated with SSRIs. Development of selective tracers for PET or SPECT imaging has made it possible to study in vivo neuroreceptors or specific binding sites noninvasively in the human brain (Eckelman 1998 Hom and Katzenellenbogen, 1997 Meltzer et al., 1998). The first successful radioligand was 11C R(+)McN5652 for PET imaging (Fig. 15.4) (Szabo et al., 1995 14047 Suehiro et al., 1994 15748). It showed excellent inhibition of 5-HT reuptake in rat brain synaptosomes (Ki 0.40 nM for inhibition of 5-HT reuptake) and moderate selectivity toward other monoamine transporters (dopamine and norepinephrine transporters (DAT and NET, respectively) Ki 23.5 and 1.82 nM, respectively) (Maryanoff et al., 1990). Specific binding of 11C R(+)McN5652 correlates well with the known density of SERT sites in the human brain (Parsey et al., 2000 Szabo et...

Cellular and subcellular localization

Root ganglia, suggesting the presence of these receptors on primary afferent fibres (Taylor etal. 1982 Ninkovic and Hunt 1985). Although useful as an H1 ligand, labelled mepyramine can also bind to non-H1 sites in liver and in some cell lines (Liu et al. 1994 Leurs et al. 1989 Hill et al. 1997). Quinine reduces some (but not all) of this binding (Hill et al. 1997), and recent knock-out studies confirm the caution which must be used with this ligand in studying H1 receptor binding outside the CNS (Yanai et al. 1998) Often overlooked is the very high affinity H1 binding exhibited by tricyclic antidepressants, which permits 11C -doxepin to label human brain receptors in living subjects (Yanai et al. 1992 b). The technique yields activity in good agreement with results from binding studies in animals (Yanai et al. 1990a), and it has been used to assess the brain penetration of systemically-administered H1 antagonists in man (Yanai et al. 1995). Other radioligands for the H1 receptor have...

Neurodegenerative Disorders Alzheimers and Parkinsons Disease

Only a few clinical trials have investigated the effects of vitamin E supplementation in patients with AD or PD, and the results were diverse (148-151). In a small clinical trial with patients with moderate AD, the effect of vitamin E alone (400 IU d for 1 mo) or in combination with vitamin C (1000 mg d) on lipid peroxidation was studied. Although supplementation with vitamin E alone was unable to decrease the oxidizability of lipoproteins in plasma and cerebrospinal fluid in vitro, a combination of vitamin E plus C decreased lipoprotein susceptibility, suggesting an antioxidant function of both vitamins in human brain (148).

Prefrontal Dependent Learning

The prefrontal cortex receives a dense serotonergic innervation from the raphe nuclei (Smiley and Goldman-Rakic 1996), which constitutes a serotonergic system. Prefrontal pyramidal neurons possess several serotonin receptor subtypes, with a particularly high density of 5-HT1A and 5-HT2A receptors (Feng et al. 2001 Jakab and Goldman-Rakic 1998). Although there is comparatively less evidence on the presence of 5-HT2C receptor mRNA in the prefrontal cortex, several studies have shown the presence of 5-HT2C receptor mRNA in the cingulate cortex or in the anterior cingulate cortex (Pompeiano et al. 1994 Hoffman and Mezey 1989). Additionally, a study in human brain showed a similar distribution of 5-HT2C receptor mRNA as has been found in rat brain, including its expression in the anterior cingulate cortex (Pasqualetti et al. 1999). 5-HT2C mRNA is expressed in the same

GABAGlutamate Glutamine Cycle

Precursor in the opposite direction owing to the lack of a neuronal anaplerotic pathway. Although it has recently been shown that carboxylation of pyruvate, presumably via mitochondrial malic enzyme, can occur in cultured cerebellar granule cells (Hassel and Brathe, 2000), the extent to which this occurs at physiological concentrations of pyruvate is disputable (Lieth et al., 2001). The closely related nonneuroactive amino acid, glutamine, has been shown to be the predominant glutamate precursor, being rapidly and extensively metabolized to glutamate in neurons (Berl and Clark, 1969 Bradford et al., 1978 Rothstein and Tabakoff, 1984 Szerb and O'Regan, 1985 Shank et al., 1989 Waagepetersen et al., 2005). Glutamine is exclusively synthesized in astrocytes by an ATP-dependent amidation of glutamate, catalyzed by the cytosolic enzyme GS (Norenberg and Martinez-Hernandez, 1979). Thus, the net flow of glutamate from neurons to astro-cytes is counteracted by a glutamine flow from astrocytes...

Other Neuromodulators Cytokines Substance P Glutamate yAminobutyric Acid and Enkephalins

Substance P receptors, particularly the neurokinin-1 (NKt) receptors, are highly expressed in brain regions, including the amygdala, septum, hippocampus, thalamus, and periaqueductal grey, that are critical to regulation of emotion and neurochemical responses to stress (153-155). Prostaglandin agonists and vanilloid receptor agonists, such as N-arachidonyl-dopamine, induce substance P release (156, 157). NKj antagonists may exert a significant part of their effects through the monoamines. Substance P and 5-HT are co-expressed in ascending raphe neurons in human brain (114). Sustained administration of an NKt antagonist increased spontaneous firing of dorsal raphe 5-HT neurons associated with reduction in 5-HT1A autoreceptor responsiveness (158). This suggests that NKt antagonists enhance 5-HT receptor activation. In addition, glutamate receptor antagonists can block the effect of NK1 agonists on firing of 5-HT neurons. This effect is blocked by NK1 antagonists and an AMPA kainate...

Serotonin Transporters SERTs

Studies using 11C McN5652 have shown, for example, increases in SERT in several cortical and subcortical regions of patients with depressive disorders 72,73 . More recently, an 18F methyl analogue of McN5652, i.e., 18F FMe-McN5652, has been developed and was found to be superior to the original 11C McN5652 in the in vivo visualization of SERT in the human brain 74,75 . Several other compounds evaluated as potential radioligands for SERT (see Fig. 8) are the benzylamines within the MADAM ADAM group (e.g., MADAM 84,85 , ADAM 86,87 , HOMADAM 88 , and EADAM 89 ), of which only 11C MADAM has been used in human PET so far ( 123I ADAM has been used in SPECT in humans). The first studies with 11C MADAM indicate that this radioligand may be as suitable as 11C DASB for the quantification of SERT in the human brain.

Human Dopamine Transporter Hdat Slc6A3 31 hDAT Cloning and Gene Organization

Libraries to clone the rat DAT (rDAT) (52,53). Elucidation of the rDAT sequence provided the tools needed to isolate the human DAT (hDAT) cDNA from human brain stem and SN libraries (54,55). The hDAT cDNA contained 5' and 3' untranslated sequence, and an open reading frame coding for a 620 amino acid protein with an estimated mol wt of approx 69,000 kDa and the 12 TMD predicted topology previously observed in GAT and NET (54,55, Fig. 1B). hDAT contains three potential N-linked glycosylation sites in the large EL between TMDs three and four (see also Chapter 10), and there is greater than 90 homology between rDAT and hDAT at the amino-acid level (54,55). Northern blot analysis revealed a single 4.2-kb mRNA in human SN (56). Southern blot analysis demonstrated that the hDAT gene (SLC6A3) is, like NET, a single copy gene, and additional studies have localized the gene to the distal short arm of chromosome 5 at 5p15.2-15.3 (54,57). Cloning of hDAT revealed the gene to span more than 64...

Research and Education in Molecular and Functional Imaging at Tohoku University

For brain research, we have mainly used 18F fluoro-L-DOPA (dopamine metabolism) 6, 7 , 11C YM9151-2 and 11C nemonapride (dopamine D2 receptors) 6, 8 , 11C benztropine (muscarinic acetylcholine receptors) 9 , and 11C doxepin (histamine H1 receptors H1R) 10 for human brain studies. Brain activation studies during running 11 and car-driving 12 have also been initiated. Various new tracers have been introduced, such as 11C BF-227, for imaging beta-amyloid deposition 13 , and 11C donepezil, for evaluating the function of acetylcholinergic nerves 14 . 11C BF-227 has recently attracted the attention of many Japanese investigators as the first domestic probe for the clinical examination of AD patients. 11C donepezil has also been used previously in clinical examinations at Tohoku University 14 (Fig. 1).

Parenteral Vasodilators

NESIRITIDE Nesiritide (natrecor), a recombinant form of human brain natriuretic peptide (BNP), is FDA-approved for treatment of dyspnea due to congestive heart failure. The natriuretic peptides atrial natriuretic peptide (ANP), BNP, and C-type natriuretic peptide are a family of endogenous hormones that possess potent natriuretic, diuretic, and vasodilator properties. BNP is secreted by ventricular cardiac myocytes in response to stretch circulating levels of BNP correlate with the severity of heart failure. In the setting of heart failure, the effects of BNP counteract the effects of AnglI and NE by producing vasodilation, natriuresis, and diuresis.

Neuroimaging Synonyms

Neuroimaging is a family of techniques used for obtaining images of the structure or the function of the human brain. Neuroimaging studies investigate structural and functional brain maturation in health or in diseases of the brain, such as schizophrenia, bipolar disorder, depression, ADHD, drug dependence, and autism. These studies often aim to find genetic and environmental markers of variance in brain structure and function over time. Through additions to diagnostic radiology, neuroimaging has broadened to become a distinct field in neuroscience. The neuroimaging techniques that are currently used in research include single-photon emission computerized tomography (SPECT), positron emission tomography (PET), distinct forms of magnetic resonance imaging (MRI) including structural and functional MRI, MR spectroscopy (MRS), and diffusion tensor imaging (DTI).

Neurotransmitter And Neuropeptide Systems Serotonergic System


5-HT-producing cell bodies in the brain are localized in the central gray, in the surrounding reticular formation, and in cell clusters located in the center, and thus the name raphe (from Latin, meaning midline) was adopted (Figure 1-3A) (discussed more extensively in Chapter 4, Chemical Neuroanatomy of the Primate Brain). The dorsal raphe (DR), the largest brain stem 5-HT nucleus, contains approximately 50 of the total 5-HT neurons in the mammalian CNS in contrast, the medial raphe (MR) comprises 5 (Descarries et al. 1982 Wiklund and Bjorklund 1980). Serotonergic neurons project widely throughout the CNS rather than to discrete anatomical locations (as the dopaminergic neurons appear to do see Figure 1-4A later in this chapter), leading to the suggestion that 5-HT exerts a major modulatory role throughout the CNS (Reader 1980). Interestingly, evidence suggests that infralimbic and prelimbic regions of the ventral medial prefrontal cortex (mPFCv) in rats are responsible for detecting...

The Macrophage Theory Of Depression

Cytokines are large hydrophilic molecules (Hamblin, 1994), their size and structure being such that passive diffusion across the blood brain barrier (BBB) is likely to be minimal (Hopkins and Rothwell, 1995). Currently, it is postulated that cytokines produced in the periphery can act on one or other circumventricular organs, such as the median eminence (ME) and the organum vasculosum laminae terminalis (OVLT) that lack a functional BBB (Hopkins and Rothwell, 1995). It has been suggested that cytokines from the periphery bind directly to glial cells on the OVLT, which in turn produce cytokines and other mediators such as prostaglandins, particularly prostaglandin E2 (PGE2). This hypothesis is consistent with the observations that peripheral IL-1 beta administration elevates PGE2 concentrations in many brain structures as assessed by in vivo microdialysis, which is maximal and most rapid at the OVLT and the medial preoptic area, and that the central increase in PGE2 precedes the onset...

Free Radicals Derived From Catecholamines

Neuromelanin Anatomy

The question then naturally arises, ''Where in the brain are these catecholamine o-quinones formed '' The cell bodies containing dopamine are located in the substantia nigra and the ventral tegmentum. These neurons release dopamine from their dendrites as well as from their axon terminals (58). Dopamine is released diffusely from an extensive network of axons mainly in the prefrontal cortex, striatum, and nucleus accumbens. Norepinephrine is released from a similar axonal network widely in the cortex which arises from cell bodies in the locus coeruleus. Adrenaline-containing neurons are located in groups C1-C3 in the medulla. These give rise to a dense innervation of medial thalamic nuclei and other limbic structures (63,69), where they are strategically placed powerfully to influence many limbic functions. The enzyme phenylethanolamine A-methyltransfer-ase (PNMT), which synthesizes adrenaline from norepinephrine, is found in human brain (46) in high concentration in the reticular...

Preparation of Isotopically Labeled Compounds

The rapid synthesis of short-lived radiolabeled (for example 11C, 18F) substances used in positron emission tomography (PET) was one of the first applications of single-mode microwave-assisted synthesis, and this area has been extensively reviewed 6 . A typical application of this technique is shown in Scheme 6.170. In recent years, considerable effort has been devoted to the design, synthesis, and pharmacological characterization of radiofluorinated derivatives of the 5-HT1A receptor antagonist WAY-100635 for the in vivo study of these receptors in the human brain by PET. 6- 18F Fluoro-WAY-100635 can be efficiently synthesized in one step from the corresponding 6-nitro precursor by nucleophilic heteroaromatic fluorination 320 . As radiofluorinating agent, the activated K 18F F-Kryptofix 222 complex was employed (Kryptofix 222 High incorporation yields were observed after 1 min of single-mode microwave irradiation of the nitro precursor in dimethyl sulfoxide solution (no reaction...

Known Effects of Drugs on Human Sexual Differentiation

It has also been reported that DES can alter sex differentiation of the human brain. Several behavioral alterations have been observed in some DES daughters 43,44 .Meyer-Bahlburg et al. 43 reported that women exposed to DES in utero were found to have less well established sex-partner relationships, and to be lower in sexual desire and enjoyment, sexual excitability, and coital functioning. In addition, Hines and Shipely 45 found that DES-exposed women showed a more masculine pattern of cerebral lateralization on a verbal task than did their sisters.

Heterodimerization Splice Variants and Isoforms

RNA splicing results in the production of a truncated 5-HT2C receptor (5-HT2Ctr) containing the N-terminus and TMDs I-III followed by 96 unique amino acids resulting from a frame shift and premature stop codon (Canton et al. 1996). In human brain tissue, 5-HT2Ctr mRNA is found in all regions containing the full-length mRNA for the 5-HT2C receptor, including hippocampus, hypothalamus, frontal cortex, striatum, and olfactory tubercle (Canton et al. 1996). The mRNA for 5-HT2Ctr represents 60 of the total 5-HT2C mRNA found in choroid plexus and 20-30 of that found in other neuronal tissues. Western blots of membrane extracts from trans-fected NIH3T3 cells revealed immunoreactive bands the predicted size of the truncated protein, indicating that mRNA encoding 5-HT2Ctr is translated into protein. Radioligand binding and inositol phosphate production were not observed in the transfected cells, indicating that 5-HT2Ctr is nonfunctional (Canton et al. 1996).

Neurotransmitter Perturbations Via PPARa Activation

The KD may be anticonvulsant via its ability to correct disturbances in neurotrans-mitter concentrations associated with epilepsy. These include alterations in excitatory neurotransmitters such as glutamate and aspartate, inhibitory neurotransmitters such as Y-aminobutyric acid (GABA), and taurine, and or neurotransmitters such as glycine that may adopt either excitatory or inhibitory roles (41). Thus, for example, the KD decreases aspartate (42) and enhances synthesis of GABA from glutamate (42). Furthermore, changes in a variety of other neurotransmitters, including dopamine, norepi-nephrine, and serotonin, may be implicated in epilepsy (41). Also, polyamines such as putrescine, spermine, and spermidine are implicated in disturbed glutamatergic neurotransmission in actively epileptogenic human brain (41). In addition, levels of neuroin-active amino acids such as glutamine and leucine play important roles in brain nitrogen balance and thus are implicated in epilepsy (42). Such...

Mechanism Of Action

While 5-HT and -adrenergic receptor adaptation remains an attractive area of research, attention has increasingly been focused on postreceptor intracellular signal transduction changes observed after long-term antidepressant treatment. Chronic administration of antidepressants has been shown to activate second-messenger systems, such as cyclic adenosine monophosphate (cAMP) and tyrosine kinase B, associated with hippocampal neurons (Duman 1998). Data derived from postmortem human brain tissue studies suggest increased levels of brain-derived neurotrophic factor (BDNF) within the hippocampus of subjects with depression who had been treated with antidepressants, compared with control subjects with depression who had been nonmedicated (Chen et al. 2001). It has been suggested that neuronal injury mediated by stress-related illnesses, such as depression and anxiety, may be reversed by antidepressant-induced increases in BDNF expression in the CNS posited to contribute to clinical response...

Classic Neurotransmitters and the Monoamine Hypothesis of Depression

During behavioral stress, LC neuronal firing is increased (129) in association with increased release of NE. This LC responsiveness is enhanced with a novel stress after chronic or prior stress. When stress exposures are repeated in situations that prevent the animal from escaping, the animal exhibits learned helplessness which is associated with the depletion of NE (130). It is thought that this depletion is due to inability of the animal to synthesize sufficient NE to replace that which is released (131). Whether such depletion occurs in human brain following the chronic stress of depression is not known.

Question And Answer Session

I presume since we can measure all of these osmolytes with MR spectroscopy in the human brain, that you now routinely use spectroscopy in your patients. DR. VERBALIS You presume wrong, but it has been done. The same kind of decreases in osmolytes shown in the animal models has also been documented in human brains at UCLA using magnetic resonance spectroscopy. But it's not being used routinely for therapeutic purposes at this time.

Peroxiredoxin Based System in Cells and Organs of the Body

Differential expression of Prdx 1 and Prdx 2 in normal human brain cell types has been detected 183 . Prdx 1 is mainly present in astrocytes, in the white matter, ependymal and subependymal cells and in the basal ganglia, substantia nigra and spinal cord, while Prdx 2 is mostly present in large neurons and axons. Both Prdx 1 and Prdx 6 are expressed in glial cells (oligodendrocytes, astrocytes and microglia), but not in neurons 183, 184 . The other Prdx isoforms (2, 3, 4, 5) are expressed in neurons 184 . Prdx 2 is abundant in vitro in type 2 astrocytes, where it might play a role in the ATP-induced stress response. Indeed, ATP in type-2 astrocytes was demonstrated to stimulate the expression of HSP60, Cu,Zn-SOD and a pi shift of Prdx 2 from the oxidized to the reduced form 185 .

Aspartoacylase Deficiency In Cd

The central nervous system contains high level of NAA (36). The concentration of NAA in the human fetus brain in utero is approximately 2.5 ol g (36), while in the normal adult human brain the level varies 8-10 ol g (36-39). The accumulation in the brain of NAA due to ASPA deficiency, and the efflux of this compound form the brain, leads to elevated urinary NAA. Thus, in Canavan disease, patients had urine NAA 1440.5 873.3 mol mmol Cr in contrast to 23.5 16.1 ol mmol Cr in normal subjects (3,14). Therefore, urinary NAA is one of the markers to determine CD. However, mild elevation of NAA with macrocephaly must not be predicted as Canavan disease, unless spongy degeneration of the brain is confirmed (30).

Vomeronasal receptors

One of the fascinating approaches to understand the processing of information in the olfactory system was developed by Axel's group in 1996 (Mombaerts et al. 1996). This was based on the assumption that if each neuron of the main olfactory system expresses a single receptor type then it would become possible to follow the route of its axon to the olfactory bulb. At that time the crucial question was how the wiring network that connects the olfactory neurons to the olfactory bulb was conceived to allow us to perceive odorants. Gene targeting was the magic word and the successful approach that linked traditional neuroanatomy to modern molecular genetics. This task initially consisted in coupling the expression of a tracing molecule with that of a given receptor. The effort was materialized by creating knock-in mice in which the sequence encoding the microtubule-associated protein, Tau, was fused to that of the P-galactosidase gene (LacZ) and the product was inserted into the OR P2 locus...

5ht Receptor Subtypes

The human 5-HT1B receptors are autoreceptors that regulate the release of 5-HT from the 5-HT terminals.24 Historically, the human versions of these receptors were included in the class of 5-HT1D receptors because it had not been clear that the animal form of the 5-HT1B receptor could be found in the human brain. The class of 5-HT1D receptors has been divided into 5-HT1Da and 5-HT1Dp receptors,25 which were recently renamed as human 5-HT1D and 5-HT1B receptors, respectively.26 The 5-HT1B is the predominant form of the 5-HT1D B family in the human brain.27 5-HT1B receptors are The human 5-HT2B was recently described. Its mRNA is widely spread in the human brain in very low levels.35 Little is known about its functional significance.


Lidow, Ph.D., is a Professor of Neuroscience at the University of Maryland, Baltimore. He received his doctoral degree in the Program in Neuroscience at Northwestern University in Evanston, IL in 1985. Upon graduation, he moved to Yale University in New Haven, CT as a postdoctoral associate at the Section of Neuroanatomy. In 1990 he became associate professor at the Section of Neurobiology at Yale University School of Medicine. In this capacity, he was invited to join the then newly organized Center in Cortical Mechanisms in Schizophrenia headed by Dr. Patricia Goldman-Rakic. Under her guidance, Dr. Lidow became interested in the role of neu-rotransmitter receptors in the etiology of schizophrenia, as well as in their role as targets of antipsychotic medications. While still being an active participant in the Yale Center in Cortical Mechanisms in Schizophrenia, Dr. Lidow now resides in Baltimore where he is a Professor of Neuroscience at the Departments of Oral and...

Dopaminergic System

Rise to axons that travel via the medial forebrain bundle to innervate the caudate nucleus and putamen (see Anden et al. 1964 Ungerstedt 1971). The DA neurons that make up the nigrostriatal circuit have been assumed to be critical for maintaining normal motor control, since destruction of these neurons is associated with Parkinson's disease however, it is now clear that these projections subserve a variety of additional functions. For example, recent evidence from human brain imaging studies indicates that a subject's ability to choose rewarding actions during instrumental learning tasks can be modulated by administration of drugs that enhance or reduce striatal DA receptor activation. This further implies that the DA reward pathway in the brain is likely convergent on many discrete brain circuits and neurotransmitter alterations, and it shows that striatal activity can also account for how the human brain proceeds toward making future decisions based on reward prediction (Pessiglione...


In summary, transient expression of the reconstituted 78-44 cDNA clone in COS-7 cells produced a pharmacological delta opioid receptor binding site in these cells. In order to confirm that the binding site indeed corresponds to a naturally occuring human delta opioid receptor sequence, PCR amplifications were performed, using human brain libraries from different sources as templates. The PCR primer pair contained the start and the stop codons of the 78x44 construct (sense PCR primer 5'GGCCCCCTCCGCC-GGCGCC-3', and antisense PCR primer 5'TGAGGCGGCACGGCCAC-CGCCGGGACC-3'). Therefore, if a library contains a full-length cDNA corresponding to our reassembled clone, a 1.1-kb amplification product should be expected. Indeed, PCR amplification of a human occipital cortex cDNA library led to isolation of a 1.1-kb PCR product, with the nucleotide


Neurotrophins can be secreted constitutively or transiently, and often in an activity-dependent manner. Observations support a model in which neurotrophins are generally secreted from the dendrite and act retrogradely at presynaptic terminals, where they act to induce long-lasting modifications (Poo 2001). Within the neurotrophin family, BDNF is a potent physiological survival factor that has also been implicated in a variety of pathophysiological conditions, such as Parkinson's disease, Alzheimer's disease, diabetic peripheral neuropathy, and psychiatric disorders (Malberg et al. 2000 Nagatsu et al. 2000 Pierce and Bari 2001 Salehi et al. 1998). In particular, a genetic variant of BDNF (Val66Met) has been associated with risk for development of mood disorders in humans, as well as with mood- and anxiety-related behaviors and response to antidepressant medications in animal models (Z. Y. Chen et al. 2006 Neves-Pereira et al. 2002 Sklar et al. 2002). Recent data also support a role for...

Neural Stem Cells

The use of stem cells in science is a highly contested and volatile subject. Numerous ethical concerns surround the use of stem cells derived from human embryos and have forced scientists to find alternative sources from which to isolate these multipotent cells. In regard to NSCs, studies have determined that neurogenesis occurs throughout adulthood and that the adult brain provides a renewable source of NSCs.16,36 These reservoirs of NSCs exhibit properties comparable to their murine counterparts. Human neural stem cells (hNSCs) have been shown to exhibit tropism towards brain pathology37 and may be optimal candidates for cell-replacement therapy for nervous system disorders. Furthermore, the ability to isolate these cells from the adult human brain raises the possibility of autologous transplantation, which circumvents certain ethical issues surrounding stem cells as well as the inherent pathogenic risks associated with exogenous cell, tissue and organ transplantation. Akin to the...


Chattopadhyay, N., Zastre, J., Wong, H. L., Wu, X. Y., & Bendayan, R. (2008). Solid lipid nanoparticles enhance the delivery of the HIV protease inhibitor, atazanavir, by a human brain endothelial cell line. Pharmaceutical Research, 25, 2262-2271. Pardridge, W. M. (1999). Non-invasive drug delivery to the human brain using endogenous blood-brain barrier transport system. Pharmaceutical Science & Technology Today, 2, 4959.


Martin E, Capone A, Schneider J, Hennig J, Thiel T. Absence of N-acetylaspartate in the human brain impact on neurospectroscopy Ann Neurol 2001 49 518-21. 55. Pan JW, Takahashi K. Interdependence of N-acetyl aspartate and high-energy phosphates in healthy human brain. Ann Neurol 2005 57 92-7.

Genetic Studies

The results of studies on GluR1 knockout mice were initially surprising. The animals have normal life expectancy and development and no detectible deficits in neuronal structure or brain anatomy (267). However, there is a striking redistribution of GluR2 subunits in hippocampal CA1 pyramidal neurons in the GluR1 knockout, so that they are largely restricted to the cell body. AMPA receptor-mediated EPSCs recorded in CA1 pyramidal neurons appear normal and contain GluR2 therefore, the small amount of GluR2 present in the dendrites in the absence of GluR1 is preferentially targeted to synapses. LTP is absent in adult mice lacking GluR1, indicating a critical role for this subunit in the expression of LTP. The lack of effect of the knockout on development and basal transmission suggests that developmental synaptic plasticity is unaffected in these animals indeed, a subsequent study showed that LTP is normal in young GluR1 knockout mice (268).

Ap Aggregation

Electron microscopy and more recently (time-lapse) atomic force microscopy analyses have greatly contributed to visualizing different Ap aggregation intermediates that are formed in vitro before formation of the mature 6- to 10-nm diameter fibrils with the characteristic cross-P structure 13-15 . The aggregation conditions in vitro are very artificial, using high concentrations of pure Ap, therefore caution is warranted in translating these data directly to the aggregation process in human brain.


There is much reason to be hopeful for a future in which neural stem cell trials heretofore only involving rodents might be translated to larger mammals and eventually humans. In rats suffering from experimental parkinsonism, a rodent model for Parkinson's disease, researchers found that human and rat NSCs injected intrastriatally into rats followed similar migratory and dopaminergic neural cell differentiation35,87,88 as in normal development. In rats with experimental intracerebral hemorrhage or transient cerebral ischemia, an application for hemorrhaging and ischemic stroke, human aNSCs injected intravascularly were found to help functional recovery by differentiating into 10 neurons and 75 astrocytes.89,90 And finally, in adult nude mice with either established experimental intracranial and or subcutaneous flank tumors of neural and nonneural origin, a potential implication for human brain tumors, intravascularly delivered aNSCs were found to target both intracranial and...

Homer Vesl

In recent years, a family of proteins has emerged that facilitate protein interactions via their PDZ (PSD-95 Discs large ZO-1) domains and that function to colocalize receptors and ion channels with their downstream signalling components. Homer proteins contain a PDZ-like EVH1 domain that interacts with metabotropic glutamate receptors (mGluRs) (Fig. 7.1e). Homer1a (H1a), also known as Vesl (VASP Ena-related gene up-regulated during seizure and LTP) was initially identified as an immediate early gene that is dynamically regulated by synaptic activity and that specifically binds to the C-terminal tail of the Gq-coupled mGluRs 1 and 5 (Brakeman et al. 1997 Kato et al. 1998). Homer proteins have been isolated from Drosophila, rat, mouse, and human brain, (Kato et al. 1998 Xiao et al. 1998) and contribute to a number of synaptic functions (for review see Xiao et al. 2000). With the exception of H1a, a rapidly inducible form of Homer, all other Homers are constitutively expressed. They...


Currently used antipsychotic drugs are usually divided into two main classes on the basis of their liability to induce neurological side effects after long-term treatment. Drugs defined as typical antipsychotics (e.g., chlorpromazine, haloperi-dol, trifluopromazine) are known to induce, following repeated administration, various extrapyramidal side effects (EPS) including Parkinson-like syndrome and tardive dyskinesia (Meltzer and Nash 1991). On the other hand, chronic treatment with atypical antipsychotic drugs (e.g., clozapine, risperidone, sertindole, zotepine) is associated with a low incidence of neurological side effects (Meltzer and Nash 1991). Moreover, atypical antipsychotic drugs do not increase plasma prolactin levels in humans (Meltzer and Nash 1991). The hypothesis that typical antipsychot-ics produce their clinical effects, as well as EPS, by blocking DA D2 receptors in the mesolimbic and nigrostriatal systems, respectively (Meltzer and Nash 1991), is now generally...


A variety of methods have been developed for frequency domain analysis (3,6,20). The simplest approach is simply to use numerical integration, although this method will work poorly when spectral overlap occurs. More sophisticated analysis methods include parametric curve-fitting routines, using various model functions (e.g. Lorentzian, Gaussian, Voigt, others (21,22)) and fitting algorithms (simplex, non-linear least squares, etc ). The most sophisticated method, and one which is becoming widely used, is the so-called linear combination model (LCModel) that fits the spectrum as a linear combination of the pure compound spectra known to exist in the spectrum (4). The LCModel is particularly attractive for several reasons (a) it makes full use of all the resonances in the molecule, (b) it is fully automated and user independent, including both baseline and phase correction, (c) with appropriate calibration data, it can give absolute metabolite concentrations, and an estimate of the...


13C spectroscopy is the most informative, yet also the least sensitive, MR measure used to study human brain. In comparison to 1H and 31P, which are effectively 100 abundant, 13C has a very low natural abundance (1.1 ). Brain studies, therefore, typically require supplementation of the 13C signal, through provision of 13C glucose (either through intravenous infusions or oral intake), or other metabolite such as 13C ketones. With commercial availability of such compounds with specific 13C labeling, spectroscopy based on this isotope has been used to track the fate of the 13C nucleus into the amino acid pools of glutamate, glutamine, and GABA (8), reflecting their rapid transport, metabolic processing through glycolysis, the tricarboxylic acid (TCA) cycle, and neurotransmitter cycling. The resonances readily visualized include the label itself, e.g., 13C glucose or 13C ketone, 13C-4, 13C-3, 13C-2 resonance positions of glutamate and glutamine, and GABA. The specific position of the...

Aging and metals

Concomitant alterations in the levels of metal ions within the human brain, possibly reflected in an age-related increase in ceruloplasmin in the superior temporal gyrus of normal individuals 40 . Furthermore, electron paramagnetic imaging has demonstrated an age-related increase in clusters of Cu and Fe ions within the brain 41 . Fe is reported to be elevated with age in several brain regions, and is particularly implicated in the onset of Parkinson's disease and Huntington's disease 42-44 . The elevated Fe is detectable with MRI procedures 45-53 . Cu is paramagnetic and therefore potentially detectable by MRI, however, there are no published studies on MRI of Cu in humans.

Tctagged compounds

A large number of different small-molecule-Tc(V)-chelate complexes have been prepared as novel radiotracers.39 These include derivatives of steroids, which are designed to target estrogen receptors expressed on breast cancers, and biological dyes, which are designed to target amyloid plaques associated with Alzheimer's disease. 99mTc TRODAT-1 (Figure 18.4),40 which is a tropane analogue containing a diaminodithiol ligand, deserves special notation as it is the first Tc complex to target specific receptors in the human brain. 99mTc TRODAT-1 has been used for imaging the central nervous system's (CNS) dopamine transporters (DAT) which is particularly useful for studying patients with Parkinson's disease.41

Conclusions on SERT

Although there are a large number of SERT inhibitors used today in the clinic as SSRIs, it was not until very recently, when 11C McN5652 was synthesized, that it was possible to study this transporter using PET. None of the selective SSRIs is suitable as a PET radioligand. Today, 11C DASB appears to be the preferred PET radioligand for SERT, although the newer compounds in the 11C MADAM series may also be well suited for imaging of SERT in the human brain.


Initially characterized on a basis of activity, the transport system was distinguished by its sodium dependency and high affinity (Km & 1-5 M) for L-Glu 28 . To date, five isoforms of the EAATs have been isolated and characterized. The first three were identified almost simultaneously GLAST (EAAT 1) 29 and GLT1 (EAAT 2) 30 , which are principally considered glial transporters, from rat brain and EAAC1 (EAAT 3) 31 , a neuronal transporter, from rabbit intestine. In addition to the subsequent identification of the three homologous transporters from human brain 32 , EAAT 4 and EAAT 5 were isolated from cDNA libraries of human cerebellum and human retina, respectively 33,34 . On the basis of substrate specificity, EAATs 1-5 are considered as members of System X AG, while molecular analysis reveals that the EAATs are members of a novel gene family Human Genome Organization solute carrier family (SLC1) that also includes the sodium-dependent neutral amino acid transporters ASCT1 and...

GSK3 and Amyloidosis

Overexpress active GSK-3P in the CNS have increased levels of beta amyloid 40 . It is believed that proteolytic processing of APP occurs by the sequential activities of P- and y-secretases, which results in the release of the beta amyloid peptide. In earlier studies, the role of GSK-3 in APP processing was attributed to an interaction with the y-secretase complex activity and presenilin-1 (PS1), a component of the y-secretase complex. PS1 was shown to directly bind GSK-3P and tau in co-immunoprecipitation experiments from human brain samples 42 . A different mechanism has been suggested by Akiyama et al., who propose that GSK-3 acts on the P-secretase pathway via blocking of Pinl interaction with phosphorylated C99Thr668, which leads to decreased turnover of C99, a product of P-secretase cleavage of APP 43 . Thus, it is tempting to speculate that GSK-3 may be the key intersection point at which Alzheimer's disease-related tau hyperphosphorylation and beta amyloid formation converge.

Concluding Remarks

There are many issues in the in vivo measurements in living human beings of NAA concentrations. It is clear that the technology for making these measurements has improved dramatically, but there is still a long way to go on this. I think a lot of the issues that come up around NAA measurements in human brain in vivo still are unresolved about improving signal to noise, improving resolution, improving sensitivity, imaging time.

Future Perspectives

Neuroimaging techniques, namely positron emission tomography (PET), fluorodeoxyglucose-positron-emission tomography (FDG-PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), functional MRI (fMRI) and diffusion tensor imaging (DTI) are increasingly used to obtain useful information not only on metabolism and rates of generation of second messengers, but also on abnormalities in brain structure and function in mild cognitive impairment (MCI) and its conversion to dementia, as well as early neurodegenerative and neuropsychiatric diseases (AD, PD, depression and schizophrenia) 76,77 . These procedures offer researchers and clinicians a new noninvasive window into the human brain and spinal cord. monitored with 11C-DASB PET and 123I-p-CIT SPECT, whereas HT1A binding can be analyzed with nC-WAY100635 PET 78 . Based on the in vivo metabolism of various radioligands, PET can be used to image brain signaling and neuroplasticity in normal human brain and...


By manipulating the redox state of the cells, e.g., by increasing the antioxidant capacity of the cells or by decreasing the pro-oxidative conditions in cells in the human brain. There are several therapeutic approaches for providing such neuroprotection, including supplementation of the patient with antioxidants, energy enhancing or anti-glutamatergic drugs. Antioxidants are used because of their ability to scavenge ROS and thus preventing damage to neurons. Since many plant-derived antioxidants are present in certain foods in different combinations, we will sometimes describe the positive effects of the foods rather than those of the isolated ingredients. In addition, energy supplementation is supposed to neuronal resistance to glutamate and ROS induced damages and initiate repair processes. Anti-glutamatergic drugs will decrease pathophysiological calcium influx and calcium-related injury including mitochondrial dysfunction. In the subsequent sections, a variety of natural and...

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