NEUROPROTECTIVE STRATEGY FOR ALZHEIMER-DISEASE - INTRANASAL ADMINISTRATION OF A FATTY NEUROPEPTIDE

Neurodegenerative diseases, in which neuronal cells disintegrate, brin g about deteriorations in cognitive functions as is evidenced in milli ons of Alzheimer patients. A major neuropeptide, vasoactive intestinal peptide (VIP), has been shown to be neuroprotective and to play an im portant role in the acquisition of learning and memory. A potent lipop hilic analogue to VIP now has been synthesized, [stearylnorleucine(17) ]VIP ([St-Nle(17)]VIP), that exhibited neuroprotection in model system s related to Alzheimer disease. The beta-amyloid peptide is a major co mponent of the cerebral amyloid plaque in Alzheimer disease and has be en shown to be neurotoxic. We have found a 70% loss in the number of n eurons in rat cerebral cortical cultures treated with the beta-amyloid peptide (amino acids 25-35) in comparison to controls. This cell deat h was completely prevented by cotreatment with 0.1 pM [St-Nle(17)]VIP. Furthermore, characteristic deficiencies in Alzheimer disease result from death of cholinergic neurons, Rats treated with a cholinergic blo cker (ethylcholine aziridium) have been used as a model for cholinergi c deficits. St-Nle-VIP injected intracerebroventricularly or delivered intranasally prevented impairments in spatial learning and memory ass ociated with cholinergic blockade, These studies suggest both an unusu al therapeutic strategy for treatment of Alzheimer deficiencies and a means for noninvasive peptide administration to the brain.