ALTERATIONS IN NEUROPEPTIDES IN AGING AND DISEASE - PATHOPHYSIOLOGY AND POTENTIAL FOR CLINICAL INTERVENTION

Marked specific and selective changes in the levels of some neuropepti des in age-related diseases, such as senile dementia of the Alzheimer (SDAT) or Lewy body (SDLT) types, Parkinson's disease, Huntington's di sease and major depressive disorder, versus normal aging have been not ed. However, the levels of most neuropeptides are normal. The only 2 p eptides consistently altered in SDAT are somatostatin and corticotroph in-releasing hormone both of which are reduced. In Huntington's diseas e, the level of substance P in the basal ganglia is reduced suggesting a preferential vulnerability of spiny neurones in this disease. In Pa rkinson's disease, substance P is attenuated in the basal ganglia whil e somatostatin is reduced in the neocortex. These and other results su ggest that substance P deficits are related to movement disorders whil e somatostatin deficits are related to cognitive impairment. SDLT is a type of dementia with features common to both SDAT and Parkinson's di sease, although the changes in neuropeptides suggest that neurochemica lly the disease is more closely related to SDAT. In major depressive d isorder, the level of corticotrophin-releasing hormone is reduced whil e there is a reciprocal increase in corticotrophin-releasing hormone r eceptors suggesting that the neurones remain functional. Potential cli nical intervention has been limited by problems such as poor penetrati on of agents into the brain and the short half-lives of neuropeptide a gonists and antagonists. However, some currently available agents may act, at least in part, through modulation of neuropeptide pathways, e. g. carbamazepine and alprazolam both modulate the corticotrophin-relea sing hormone system in animals, and both have clinically proven antide pressant activity.