Aliphatic N-methylpropargylamines as potential neurorescue agents.

ABSTRACT

Several clinical investigations have indicated that R-deprenyl, a typical monoamine oxidas B inhibitor, delays the progression of Parkinson's and Alzheimer's disease. A number of aliphatic N-methylpropargylamines, such as R-2-hexyl-N-methylpropargylamines (R-2HxMP), have been found to be highly potent, irreversible, selective, MAO-B inhibitors both in vitro and in vivo. These aliphatic propargylamines do not affect noradrenaline of dopamine uptake and are chemically without an amphetamine moiety and therefore do not exhibit any amphetamine-like effects. They are capable of protecting mouse striatal dopamine neurons against MPTP-induced toxicity in the caudate, against MK-801-induced apoptosis in the retrosplenial cortex and against DSP-4-induced depletion of naradrenergic axons. They rescue hippocampal neurons in rodents following kainate-induced neuronal damage. They block the expression of heat shock protein (HSP70) and delayed c-Fos expression in hippocampal CA1 region as elicited by kainate. Confocal microscopy also revealed prevention of neuronal damage in hippocampal slices under hypoxia-hypoglycemia conditions. Aliphatic N-methylpropargylamines may be useful in the treatment of neurodegenerative disorders. The mechanism and site of action of the neurorescue effect of these propargylamines, however, remains to be established.