PROTECTION BY PROSTAGLANDINS FROM GLUTAMATE TOXICITY IN CORTICAL-NEURONS

The growing evidence that glutamate may be an important agent mediatin g ischemic damage to neurons, led us to investigate the possible prote ctive effects of pharmacological agents against glutamate in a model s ystem of cortical neurons. In this study we examined, in particular, t he cytoprotective effect of prostaglandins. Experiments were carried o ut 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 abs ence of various pharmacological agents including prostaglandins (PGD(2 ), PGE(1), PGE(2), PGF(2 alpha), PGI(2), 6-Keto-PGF(1 alpha), carba-TX A(2), carba-PGI(2) and PGF(2 alpha)-methylester). Increase in lacticod ehydrogenase (LDH) release into the culture medium has been measured a s 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 c ells. The protective activity of oxypurinol, amflutizole, superoxide d ismutase, N-G-nitro-L-arginine and quinacrine, also suggests that xant hine oxidase activation, the generation of superoxide radical, and nit ric oxide, as well as phospholipase A(2) stimulation are responsible f or neuron injury (i.e. LDH release). All the tested prostaglandins, ex cept PGF(2 alpha)-methylester, afforded sigificant protection at conce ntrations between 0.1 and 10 mu M. The order of potency of the prostan oids 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 tha t they did not inhibit free radical-related membrane damage. The mecha nism by which prostaglandins of various series counteract the cytotoxi c action of glutamate is not yet elucidated, but because free carboxyl ic groups are essential for the effect, it is possible that the protec tive action involves lipid fatty acid metabolism. This effect could ha ve pathophysiological significance since prostaglandins are produced a t micromolar concentrations in post-ischaemic brain.