fg-9041 and Hypoglycemia

The effects of nitric oxide (NO) synthase inhibitors on the hypoxia/hypoglycemia-induced decrease in CA1 presynaptic fiber spikes elicited by stimulation of the Schaffer collaterals were investigated using rat hippocampal slices. Drugs were added to normal medium for 10 min before incubation under hypoxic/hypoglycemic conditions (15 min), and after a 3-h washout, the CA1 presynaptic potential was measured. Treatment with NG-nitro-L-arginine methyl ester but not with NG-nitro-D-arginine methyl ester produced a concentration-dependent attenuation of the hypoxia/hypoglycemia-induced decrease in presynaptic fiber spikes. In contrast, treatment with precursors of NO in the arginine-to-NO pathway, such as sodium nitroprusside, S-nitro-N-acetylpenicillamine and N-morpholino sydnonimine exacerbated the 15-min hypoxia/hypoglycemia-induced decrease in the CA1 presynaptic potential. The neuroprotective effect of NG-nitro-L-arginine methyl aster was significantly attenuated by co-treatment with L-arginine. The present results suggest a facilitatory role of NO production in hypoxia/hypoglycemia-induced presynaptic dysfunction in CA1 regions of hippocampal slices.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Electrophysiology; Hippocampus; Hypoglycemia; Hypoxia, Brain; In Vitro Techniques; Male; Molsidomine; Nerve Fibers; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Penicillamine; Quinoxalines; Rats; Rats, Wistar; Receptors, Presynaptic; S-Nitroso-N-Acetylpenicillamine; Vasodilator Agents

Neuron-enriched cultures from embryonic rat cerebral cortex were exposed to hypoxia and hypoglycemia, and the resulting cellular injury was quantified by measuring lactate dehydrogenase (LDH) release, which was maximal after 20-24 h. The increase in LDH release produced by hypoxia/hypoglycemia was prevented by N-methyl-D-aspartate (NMDA) antagonists, but not by three classes of drugs thought to modulate glutamate release: Ca2+ channel antagonists (nimodipine, omega-conotoxin GVIA, omega-agatoxin-IVA), KATP channel activators (cromakalim, diazoxide), and glutamate transport inhibitors (dihydrokainate, DL-threo-beta-hydroxyaspartate).

Topics: Animals; Aspartic Acid; Benzopyrans; Calcium Channel Blockers; Cell Hypoxia; Cells, Cultured; Cerebral Cortex; Cromakalim; Diazoxide; Embryo, Mammalian; Glutamates; Hypoglycemia; Kainic Acid; Kinetics; L-Lactate Dehydrogenase; Neurons; Potassium Channels; Pyrroles; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptic Transmission; Time Factors

Rat cerebellar granule cells, when subjected to a glucose-free environment for 4 h, developed extensive degeneration of neuronal cell bodies and their associated neurite network over the following 24 h. This neuronal damage was quantitated with a colorimetric assay using the metabolic dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Hypoglycemic neuronal injury could be markedly reduced by the presence of both competitive (3-(+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and non-competitive (phencyclidine) N-methyl-D-aspartate receptor antagonists, but not by kainate/quisqualate preferring antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 6,7-dinitroquinoxaline-2,3-dione. Glucose deprivation neuronal injury was also reduced by adding glutamate-degrading enzymes to the incubation medium. Monosialoganglioside GM1, but not its asialo derivative (lacking sialic acid), was also effective in protecting against hypoglycemic neurodegeneration when included during the period of glucose deprivation. These results suggest that the neuronal injury to cerebellar granule cells resulting from glucose deprivation is mediated predominantly by activation of the N-methyl-D-aspartate type of excitatory amino acid receptor, perhaps through the action of endogenously released glutamate. Furthermore, the monosialoganglioside GM1, a member of a class of naturally occurring sialoglycosphingolipids, is able to attenuate this neuronal injury--as already observed for glutamate neurotoxicity and anoxic neuronal death in cerebellar granule cells. Gangliosides may thus prove to be of therapeutic utility in excitatory amino acid-associated neuropathologies.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cerebellum; G(M1) Ganglioside; Gangliosides; Hypoglycemia; Nerve Degeneration; Neurons; Piperazines; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate