Comparative Effects of Cholinesterase Inhibitors on Glutamate-Induced Neuronal Cell Death

Abstract

Our earlier studies have shown that glutamate-induced neuronal cell death can be reduced by pretreatment with Huperzine A (Hup-A) in enriched primary neurons. These effects seem to be caused by blockage of the NMDA receptor-mediated calcium ion influxes. Hup-A is a reversible inhibitor of cholinesterase (ChEI) with a very high affinity for acetylcholinesterase as compared to butyrylcholinesterase. In the present studies we have investigated the relative potencies of other ChEIs for protecting neurons from excitatory amino acid (EAA)-induced toxicity. The ChEIs used in these studies were Hup-A, tacrine, E2020, physostigmine and dimethyl Hup-A (DMH). The cells were pretreated with graded concentrations of ChEI and then challenged with either glutamate or NMDA. Viability of the neuron was assessed after 24 hours by MTT reduction assay and in some cases also by measuring extra-cellular LDH activity. The results have shown that all these inhibitors protected the primary neurons in a dose dependant manner. However the degree of protection varied. The highest protection offered was by Hup-A followed by DMH, physostigmine, E2020, and the least protection was offered by tacrine. The present data suggest that the neuronal protection against EAA-induced cytotoxicity offered by various ChEIs is independent of their efficacy as ChE inhibitors.