PROTECTION BY PROSTAGLANDINS FROM GLUTAMATE TOXICITY IN CORTICAL-NEURONS

The growing evidence that glutamate may be an important agent mediating ischemic damage to neurons, led us to investigate the possible protective effects of pharmacological agents against glutamate in a model system of cortical neurons. In this study we examined, in particular, the cytoprotective effect of prostaglandins. Experiments were carried out in vitro by using rat cortical neurons in culture for 10 days. They were incubated for 3h with glutamate (10 mu M) in the presence or absence of various pharmacological agents including prostaglandins (PGD(2), PGE(1), PGE(2), PGF(2 alpha), PGI(2), 6-Keto-PGF(1 alpha), carba-TXA(2), carba-PGI(2) and PGF(2 alpha)-methylester). Increase in lacticodehydrogenase (LDH) release into the culture medium has been measured as an index of cell injury. When neurons were incubated with glutamale they released LDH due to NMDA-receptor activation since D-L-2-amino-5-phosphonovaleric acid, a specific receptor antagonist, protected the cells. The protective activity of oxypurinol, amflutizole, superoxide dismutase, N-G-nitro-L-arginine and quinacrine, also suggests that xanthine oxidase activation, the generation of superoxide radical, and nitric oxide, as well as phospholipase A(2) stimulation are responsible for neuron injury (i.e. LDH release). All the tested prostaglandins, except PGF(2 alpha)-methylester, afforded sigificant protection at concentrations between 0.1 and 10 mu M. The order of potency of the prostanoids was: PGF(2 alpha) = PGE(2) > Carba-TXA(2) > PGE(1) > PGD(2) > PGI(2) = Carba-PGI(2) > 6-Keto-PGFl(alpha). Additional experiments showed that prostaglandins did not compete for the NMDA binding site and that they did not inhibit free radical-related membrane damage. The mechanism by which prostaglandins of various series counteract the cytotoxic action of glutamate is not yet elucidated, but because free carboxylic groups are essential for the effect, it is possible that the protective action involves lipid fatty acid metabolism. This effect could have pathophysiological significance since prostaglandins are produced at micromolar concentrations in post-ischaemic brain.