P. Pauwels, H. P. van Assouw, L. Peeters
Dec 1, 1992
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Synapse
Abstract
The neuroprotective properties of the cognitive enhancer sabeluzole were investigated in rat brain neuronal cultures derived from the hippocampal formation of 17‐day‐old rat embryos. Measurement of the neuronal cytoskeletal microtubule‐associated protein, MAP2, was used to assess survival of neurons after exposure of neuronal cultures to glutamate. MAP2 was quantified in neuronal cell homogenates by means of an enzyme‐linked immunosorbent assay (ELISA) using a mouse monoclonal MAP2 antibody, peroxidase‐labeled goat anti‐mouse Jg antiserum, and 2,2′‐azido‐di‐[3‐ethylbenzthiazoline] sulphonate (ABTS) as substrate. Exposure of 7‐day‐old neuronal cultures to 1mM glutamate for 16 hours led to a three‐fold increase in released lactate dehydrogenase (LDH) and a 40% decrease in cellular MAP2 content. Acute treatment of neuronal cultures with 10m̈M sabeluzole yielded a 40% drop in released LDH induced by glutamate. Cultures treated chronically with 0.1 m̈M sabeluzole on days 1 and 4 in culture showed, after 1 week in culture, a MAP2 content and total LDH activity that was not different from control cultures. A 16‐hour exposure to 1mM glutamate did not induce LDH release or changes in MAP2 levels in sabeluzole‐treated cultures. A single treatment with 0.1 m̈M sabeluzole between day 1 to 5 induced a 70–80% drop in glutamate‐induced released LDH in 7‐day‐old neuronal cultures. Full and partial neuronal protection after chronic sabeluzole treatment at 0.1m̈M was also observed for neurotoxicity induced by 5mM N‐methyl‐D‐aspartate (NMDA) and 1mM kainic acid or 30 m̈M veratridine, respectively. Within a series of compounds such as Ca++and Na+ channel antagonists, glutamate receptor antagonists and various neurotransmitter receptor antagonists, sabeluzole, chronically given, were the most potent for inhibition of released LDH induced by 1mM glutamate (IC50‐ value: 34 ± 13nM). In conclusion, chronic sabeluzole treatment protects cultured rat brain neurons from excitotoxic aggression. © 1992 Wiley‐Liss, Inc.