MEMANTINE STIMULATES INOSITOL PHOSPHATES PRODUCTION IN NEURONS AND NULLIFIES N-METHYL-D-ASPARTATE-INDUCED DESTRUCTION OF RETINAL NEURONS

Whereas carbachol, noradrenaline, serotonin and memantine stimulated inositol phosphates production and calcium mobilization in 3-5 day old rabbit retinal cultures, only carbachol and noradrenaline were effective when 25-30 day old cultures were used. The older retinal cultures contain only Muller cells which shows that the memantine and serotonin effects on the 3-5 day old cultures are specifically associated with neurones. While the carbachol, noradrenaline and serotonin effects were respectively blocked by atropine, prazosin and ketanserin, none of these substances influenced the memantine responses. In all areas of the rat brain which were analysed, the effectiveness of memantine, noradrenaline and carbachol on the stimulation of inositol phosphates production was similar. However, in the rabbit retina, as opposed to the rat brain slices, carbachol had a more pronounced influence than noradrenaline in stimulating inositol phosphates production. Chick retina exposed to N-methyl-D-aspartate, quisqualate, glutamate or kainic acid resulted in cytopathological damage to cell bodies in the outer nuclear layer. The N-methyl-D-aspartate effect was nullified by memantine and MK-801 but not by kynurenic acid. In contrast the kainic acid-induced damage was specifically antagonized by kynurenic acid. The present results show that memantine influences the metabolism of inositol phosphates in neurones but not glial (Mutter) cells and appears to counteract the N-methyl-D-aspartate induced cytopathological damage. How these two effects of memantine are interrelated and whether they are involved in the described beneficial therapeutic observations of memantine (as in dementia) remains to be established.