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 microM) in the presence or absence of various pharmacological agents including prostaglandins (PGD2, PGE1, PGE2, PGF2 alpha, PGI2, 6-Keto-PGF1 alpha, carba-TXA2, carba-PGI2 and PGF2 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 glutamate 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, NG nitro-L-arginine and quinacrine, also suggests that xanthine oxidase activation, the generation of superoxide radical, and nitrix oxide, as well as phospholipase A2 stimulation are responsible for neuron injury (i.e. LDH release). All the tested prostaglandins, except PGF2 alpha-methylester, afforded significant protection at concentrations between 0.1 and 10 microM. The order of potency of the prostanoids was: PGF2 alpha = PGE2 > Carba-TXA2 > PGE1 > PGD2 > PGI2 = Carba-PGI2 > 6-Keto-PGF1 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Cazevieille
C
C
Laboratoire de Physiologie Cellulaire, Université Montpellier I, Faculté de Pharmacie, France.
Muller
A
A
Meynier
F
F
Dutrait
N
N
Bonne
C
C
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D009474:Neurons / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018377:Neurotransmitter Agents; D011453:Prostaglandins; D018698:Glutamic Acid