C. Cazevieille et al., PROTECTION BY PROSTAGLANDINS FROM GLUTAMATE TOXICITY IN CORTICAL-NEURONS, Neurochemistry international, 24(4), 1994, pp. 395-398
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.