Alzheimers Disease

AD is marked by a progressive loss of cognitive and other CNS functions and is a growing problem in our aging society. AD targets the cholinergic neurons of the basal forebrain that provide the major cholinergic innervation to the hippocampus, amygdala, and cortex that are involved in many aspects of memory, cognition, and behavior.181 The current mainstays of AD treatment are cholinesterase inhibitors that block the enzyme that degrades acetylcholine (ACh) released from these neurons, thereby helping maintain cholinergic tone. Another approach to enhancing cholin-ergic tone is to mimic ACh actions, such as with Ml muscarinic receptor agonists.182 This mechanism may also modulate production of p-amyloid tangles that represent neuropathological hallmarks of the AD process. Muscarinic agonists such as xanomeline have shown efficacy in improving cognitive and behavioral deficits in AD183 but produce intolerable cholinergic side effects, perhaps due to lack of selectivity. The development of positive modulators of muscarinic receptors that interact with allosteric sites on the receptors may provide more opportunity for selectivity, and continues to be an active area of research for treating Alzheimer's disease.184

Increasing the release of ACh from neuronal terminals may achieve a similar increase in cholinergic tone and is a potential therapeutic mechanism for GPCR ligands currently in development for the treatment of cognitive disorders. For example, 5HT6 antagonists increase the release of neurotransmitters, including ACh, in rat frontal cortex,185 5HT6 antagonists enhance spatial learning retention in the rodent water maze model102 186 and reverse anticholinergic-induced memory deficits in rodent learning models.185 187 188 This suggests that modulation of 5HT6 may be effective in enhancing cognitive functions, although failure to reproduce these effects has also been reported.189 The 5HT6 antagonist, SB-271046, also improved cognitive deficits in aged rats, further suggesting a role for 5HT6 antagonists in the treatment of dementia.187 5HT1A antagonists also reverse anticholinergic-induced deficits in performance of learning and memory tasks in some, but not all, animal models. This suggests that other members of the 5HT receptor family may provide additional therapeutic approaches to cognition enhancement in AD.190

All About Alzheimers

All About Alzheimers

The comprehensive new ebook All About Alzheimers puts everything into perspective. Youll gain insight and awareness into the disease. Learn how to maintain the patients emotional health. Discover tactics you can use to deal with constant life changes. Find out how counselors can help, and when they should intervene. Learn safety precautions that can protect you, your family and your loved one. All About Alzheimers will truly empower you.

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