A dysfunction of the cholinergic system occurs in some degenerative diseases of the brain, like Alzheimer's disease. The progression of Alzheimer's disease is accompanied by:
• a strong reduction in the activity of acetylcholine esterase in several cerebral structures, especially in the cortex, the hippocampus and the amygdala;
• a reduction in the biosynthesis of acetylcholine;
• a reduction in the high-affinity uptake of choline;
• a loss of cholinergic neurons in the nucleus basalis of Meynert;
• a loss of nicotinic receptors in the cortex and in the hippocampus, in contrast to the muscarinic receptors which show no obvious reduction.
The neurotoxic effect of neurofibrillary tangles and beta-amyloid plaques are hallmarks of Alzheimer's disease. Disease-modifying approaches which might lead to neuroprotection and enhanced survival of neurons are at the focus of therapeutic strategies.
Recent data suggest a role for cholinergic stimulation in counteracting beta-amyloid toxicity. Especially, the al nicotinic acetylcholine receptor is considered to be a strategic target for inducing neuroprotective effects. Galantamine, which is a modest acetylcholinesterase inhibitor in addition to being an allosteric modulator of nicotinic acetylcholine receptors, has therefore been applied in preclini-cal studies with promising effects; and new disease-modyfing agents capable of stimulating the al nicotinic receptor system are of further interest to discern potential neuropretection in this degenerative disease.
Imbalance of the cholinergic system also seems to be involved in Parkinson's disease. This is apparent from the hyperactivity of cholinergic interneurons in the striatum, following the reduction of the dopaminergic influence. Further more, the cholinergic system is impaired in Huntington's chorea, since an essential feature of this inherited disease is a characteristic loss of cholinergic in-terneurons in the striatum.
In the periphery, the most prominent disease which involves the cholinergic transmission is Myastenia gravis, an autoimmune disease which manifests itself at the motor endplate. Autoantibodies directed to the nicotinic receptors of motor endplates produce a masking of the receptors, which finally leads to their degradation. The functional consequence is a reduction of cholinergic transmission at skeletal muscles which is causal for the most prominent clinical sign of severe muscle weakness in these patients. The inhibition of acetylcholine esterases in order to prolong the action of endogenous acetylcholine is one of the therapeutical regimes used to treat this disease.
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