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importance is huperzine, a lykopodium alkaloid isolated from the Chinese herb Huperiza serrata.

Tacrine was the first reversible acetylcholinesterase inhibitor to be studied and approved for the treatment of AD, and is about four times more potent in its action on butyrylcholinesterase than on acetylcholinesterase. The therapeutic effects of tacrine do not seem to be correlated closely with its anticholinesterase activity, so it is thought that other neurochemical actions of the drug may be contributing to its behavioral activity. Tacrine is also known to produce problematic side effects in many patients, including hepatotoxicity.

Physostigmine is an alkaloid isolated from the seed of a perennial plant of West Africa (the Caliber bean), and is classified as a carbamate acetylcholinesterase and reversible inhibitor (Giacobini 2000). Physostigmine is the most potent of the carbamate derivatives, which also includes rivastigmine. Both of these agents are more selective for butyrylcholinesterase than for acetylcholinesterase.

Rivastigmine is a pseudo-irreversible cholinesterase inhibitor, and is found to specifically inhibit the acetyl-cholinesterase subtype found primarily in the hypothalamus and cortex. This particular subtype is implicated in the accumulation and maturation of amyloid plaque.

Donepezil was approved as a treatment for AD in 1996, and is known to be more selective for acetylcholinesterase versus butyrylcholinesterase (Giacobini 2000). Donepezil is a reversible inhibitor but due to its long pharmacoki-netic half-life (about 100 h), it produces long lasting inhibition. The rate of onset of pharmacodynamic activity, however, is slow because the drug is relatively slowly absorbed.

Galantamine is a reversible acetylcholinesterase and competitive inhibitor, but unlike other agents, can also act on nicotinic receptors by allosteric modulation. As it is a weak cholinesterase inhibitor, this allosteric modulation of nicotinic receptors has been postulated to be a significant contributor to the activity of the drug. It has been proposed that modulation as opposed to agonism may protect against down regulation of post-synaptic receptors and thus allow the drug to have a more sustained action.

Huperzine is a potent, highly specific, reversible inhibitor of acetylcholinesterase. It has been found that the potency of Huperzine A is similar or superior to other inhibitors currently being used in the treatment of AD, based on in vitro and in vivo comparison studies.

Behavioral Effects of Acetylcholinesterase Inhibitors

Due to the extensive distribution of cholinergic pathways in the brain, anticholinesterase activity affects a wide range of behavior in animals and in humans. Although acetyl-choline was not identified as a brain transmitter until 1914, physostigmine was isolated as a natural product and used as clinical therapy as early as 1877 (Giacobini 2000). The most recent neuropharmacological application of these agents has been as antidementia drugs. Tacrine was the first drug approved for the treatment of AD and was shown to improve memory, language, praxis, and activities of daily living.

In patients with AD, it is thought that cholinergic deficits in limbic and paralimbic structures contribute to the development of abnormal behavior, and human pharmacology data support the concept that stabilization of cholinergic function could improve both behavioral symptoms and cognitive deficits (Giacobini 2000). Most clinical trials have shown that acetylcholinesterase inhibitors improve scores on cognitive subscales of the AD Assessment Scale, the Mini-Mental State examination, and global scales such as the Clinical Interview-Based Impression of Change (CIBIC). For noncognitve domains, scales such as the AD Assessment Scale (ADAS-noncog) and the Neuropsychiatric Inventory (NPI) scale have most consistently demonstrated the ability of AChEIs to improve noncognitive behavioral problems including apathy, disinhibition, abberant motor behaviors, and anxiety. These agents temporarily improve, stabilize, or reduce the rate of decline in memory and other intellectual functions relative to placebo.

Comparison Between Acetylcholinesterase Inhibitors

In a meta-analysis done by Hansen et al. the affects of three major acetylcholinesterase inhibitors on behavior and cognition in 26 different studies were reviewed. Two trials directly comparing donepezil and galantamine showed conflicting results; the longer 52-week, fixed dosed trial found no significant differences between the agents in cognition for treated patients, while the shorter 12-week trial using flexible doses of drug showed significant differences in cognition and function favoring donepezil. In a 2-year double blinded randomized trial comparing flexible doses of donepezil and rivastigmine, treated patients had similar favorable changes in cognition and behavior as measured by Severe Impairment Battery (SIB) and Neu-ropsychiatric Inventory (NPI). Patients treated with rivas-tigmine had significantly better functional and global assessment outcomes. In a shorter, 12-week open label trial comparing flexible doses of donepezil and rivastigm-ine, no statistically significant differences were seen in cognition. For donepezil, rivastigmine, and galantamine, Hansen et al. concluded that the meta-analyses of placebo-controlled data support modest overall benefits for stabilizing or slowing decline in cognition, function, behavior, and clinical global change (Hansen et al. 2008). In another review of 24 trials, it was found that donepezil improved cognition and global functioning for patients with AD and ► vascular dementia. In 10 studies investigating galantamine versus placebo, there was consistent evidence that patients being treated with galantamine showed a positive effect on cognition and global assessment. There is less consistent evidence for a significant difference in cognition for tacrine versus placebo.

Treatment with cholinergic agents may also show beneficial behavioral and cognitive responses in other disorders with cortical cholinergic abnormalities such as

► Lewy body dementia, Parkinson's disease with dementia, olivopontocerebellar atrophy, vascular dementia, Down's syndrome, and traumatic brain injury. It has also been hypothesized that the cognitive deficits seen in

schizophrenia could be in part secondary to dysfunction within the cholinergic system. Although findings have been negative, this concept is under investigation with the use of cholinergic agents, e.g., nicotinic agonists, as possible treatments.

Cholinesterase inhibitors have also been reported to prevent and/or reduce common behavioral disturbances seen in patients with AD, including apathy, agitation, and

psychosis (hallucinations and delusions). Visual hallucinations and apathy are the most commonly reduced symptoms. Anxiety, disinhibition, agitation, depression, delusions, and aberrant motor behavior are also found to improve in some studies but not all.

Factors that may Affect Acetylcholinesterase Effect For procholinergic drugs, as the dose is increased, efficacy increases. However, side effects may become a limiting factor more rapidly than loss of efficacy, with an upside down U-shaped curve describing the relationship between cholinergic stimulation and cognitive benefit. Also, due to the phasic properties of cortical acetylcholine function, it is often difficult for increased acetylcholine in the synaptic cleft to result in stimulation of post-synaptic receptors independently from pre-synaptic activity. The ability of pre-synaptic neurons to respond to signaling may also be reduced by excessive autoreceptor stimulation. A wide range of response to treatment is seen, and may be due to variations in cholinergic deficit between patients. There maybe a potential role for the ► apolipoprotein E4 genotype, as its presence is linked with late-onset AD, though the effect of this allele on the degree of Alzheimer neuro-pathology is not clearly understood. These individuals have less brain ► choline acetyltransferase and nicotinic receptor binding, which may contribute to developing cognitive dysfunction from cholinergic deterioration. It is clear that differences in age, disease severity, and genotype may all influence ► cholinergic deficits, and thus, the response to acetylcholinesterase therapy will vary between individuals.

Contradictions Regarding Effects of Acetylcholinesterase Inhibitors on Human Cognitive Functioning

A review of the effects of acetylcholinesterase inhibitors on cognitive functioning and performance in humans demonstrates both performance enhancement and impairment. A careful look at the nature of these disparate studies reveals clues to understanding the seemingly contradictory nature of research in this area.

Studies which tend to show impairment generally use normal unimpaired subjects. These studies tend to conclude that blocking acetylcholinesterase does not improve cognitive functioning and may impair it. By contrast, studies which tend to show improvement generally utilize clinical populations or normal subjects who have been artificially impaired. These studies generally demonstrate and/or conclude that acetylcholinesterase inhibitors have cognitive-enhancing effects. These disparate results can be resolved by considering that the findings reflect the differing populations utilized for the experiments. These populations can be expected to show quite different responses to nicotine based on principles of rate dependency or baseline effects of cholinergic agents (e.g., the Yerkes-Dodson principal) (Fig. 1). Cognitive performance can be envisioned as a parabolic function related to choliner-gic stimulation with intermediate levels of stimulation producing optimal performance and either low or high levels of stimulation impairing performance. If an individual subject who is performing suboptimally due to a disease state or impairment (e.g., AD), his performance will be enhanced by increased cholinergic stimulation via acetylcholinesterase inhibition (Fig. 1a). However, if an individual subject is already performing at or near their optimal level of performance, increasing cholin-ergic stimulation following acetylcholinesterase inhibitor administration will produce deterioration in cognitive functioning (Fig. 1b). The same analysis may apply if the individual is normal but the task demands are severe.

Acetylcholinesterase and Cognitive Enhancement. Fig. 1.

Effects of cholinergic stimulation through acetylcholinesterase blockade are dependent on baseline performance and are subject to nonlinear effects. (a) Baseline performance is low and cholinergic augmentation through produces improvement in performance. (b) Baseline performance is normal/high and cholinergic augmentation impairs performance.

If the task is demanding enough in terms of attention, especially over a period of time, then the individual may move back to the left in terms of the performance curve and optimal performance may require enhanced cholin-ergic stimulation.

Studies of normal volunteers are thus unlikely to show cognitive improvement with cholinergic stimulation due to the fact that these individuals are likely to be operating at or near their optimal level of performance, particularly in the setting of experimental paradigms with pre-train-ing for cognitive tasks, financial incentives, etc.

The preponderance of evidence is that stimulation of cholinergic receptors is most easily detected by effects on attentional systems and to some extent psychomotor speed. The most well-documented effect of cholinergic augmentation is on intensifying or sustaining attention to stimuli or tasks over a prolonged period of time. In addition, there is evidence from studies of individuals with disorders such as schizophrenia and ADHD that nicotinic cholinergic stimulation enhances selective attention, sensory detection, and inhibitional processes in attention. Positive effects of nicotinic stimulation, via acetylcholinesterase inhibitors on learning in memory may be mediated by effects on attentional functioning. Learning and memory require acquisition, encoding, storage, and retrieval. However, attention is the "front end'' of this process, and adequate attentional functioning is a primary requirement for higher order processing.

Attention and related processes may be thought of as an endophenotype for cholinergic stimulation and consequently drug development. Attention, central processing impairment, and executive dysfunction may be orthogonal to the underlying neuropsychiatric diagnoses and should be considered as an independent target for drug development across diagnostic categories. Particular attentional deficits in different diagnoses may still respond to cholinergic stimulation with acetylcholinesterase inhibitors, however, the parameters for assessing improvement may be quite different between disease states and will require careful attention to particular specific agents, dosing regimens, and outcome measures for experimental studies. Paying careful attention to the issue of baseline dependency in treatment response will be vital to ensuring appropriate interpretation of experimental results, both for studies of normals and individuals with disease states. Targeting specific populations that are already impaired is much more likely to reveal potential benefits of cholinergic stimulation. Studies of normal or unimpaired individuals with acetylcholinesterase inhibitors are unlikely to show cognitive benefits except under extreme task demands.

Cross-References

► Cognitive Enhancers: Role of the Glutamate System

► Dementias and other Amnestic Disorders

► Mild Cognitive Impairment

► Muscarinic Agonists and Antagonists

► Nicotinic Agonists and Antagonists

References

Bartus RT, Dean RL III et al (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408-417 Drachman D (1977) Memory and cognitive function in man: does the cholinergic system have a specific role? Neurology 27:783-790 Dumas JA, Saykin AJ et al (2008) Nicotinic versus muscarinic blockade alters verbal working memory-related brain activity in older women. Am J Geriatr Psychiatry 16:272-282 Foldi NS, White RE et al (2005) Detecting effects of donepezil on visual selective attention using signal detection parameters in Alzheimer's disease. Int J Geriatr Psychiatry 20(5):485-488 Giacobini E (ed) (2000) Cholinesterases and cholineserase inhibitors.

Martin Dunitz Ltd., London Hansen RA, Gartlehner G et al (2008) Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Clin Interv Aging 3(2):211-225

Newhouse PA, Sunderland Tet al (1988) The effects of acute scopolamine in geriatric depression. Arch Gen Psychiatry 45:906-912 Newhouse PA, Potter A et al (1994) Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. Neuropsy-chopharmacology 10(2):93-107 Newhouse PA, Potter A et al (2004) Effects of nicotinic stimulation on cognitive performance. Curr Opin Pharmacol 4:36-46 Potter AS, Newhouse PA (2004) Effects of acute nicotine administration on behavioral inhibition in adolescents with attention-deficit/hyper-activity disorder. Psychopharmacology 176(2):182-194 Sarter M, Hasselmo ME et al (2005) Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection. Brain Res Rev 48:98-111 Sperling R, Greve D et al (2002) Functional MRI detection of pharmacologically induced memory impairment. Proc Natl Acad Sci 99(1):455-460

Thiel CM, Zilles K et al (2005) Nicotine Modulates Reorienting of Visuospatial Attention and Neural Activity in Human Parietal Cortex. Neuropsychopharmacology 30:1-11 Vanneri A, McGeown WJ et al (2009) Responders to ChEI treatment of Alzheimer's disease show restitution of normal regional cortical activation. Curr Alzheimer Res 6:97-111 Warburton DM, Rusted JM (1993) Cholinergic control of cognitive resources. Neuropsychobiology 28(1-2):43-46

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