2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and 7-chlorokynurenic-acid

Hypoglycemia is a common adverse event and can injure central nervous system (CNS) white matter (WM). We determined whether glutamate receptors were involved in hypoglycemic WM injury.. Mouse optic nerves (MON), CNS WM tracts, were maintained at 37°C with oxygenated artificial cerebrospinal fluid (ACSF) containing 10mM glucose. Aglycemia was produced by switching to 0 glucose ACSF. Supramaximal compound action potentials (CAPs) were elicited using suction electrodes, and axon function was quantified as the area under the CAP. Amino acid release was measured using high-performance liquid chromatography. Extracellular lactate concentration ([lactate(-)]o) was measured using an enzyme electrode.. About 50% of MON axons were injured after 60 minutes of aglycemia (90% after 90 minutes); injury extent was not affected by animal age. Blockade of N-methyl-D-aspartate (NMDA)-type glutamate receptors improved recovery after 90 minutes of aglycemia by 250%. Aglycemic injury was increased by reducing [Mg(2+)]o or increasing [glycine]o , and decreased by lowering pHo , expected results for NMDA receptor-mediated injury. pHo increased during aglycemia due to a drop in [lactate(-)]o. Aglycemic injury was dramatically reduced in the absence of [Ca(2+)]o. Extracellular aspartate, a selective NMDA receptor agonist, increased during aglycemia ([glutamate]o fell).. Aglycemia injured WM by a unique excitotoxic mechanism involving NMDA receptors (located primarily on oligodendrocytes). During WM aglycemia, the selective NMDA agonist aspartate is released, probably from astrocytes. Injury is mediated by Ca(2+) influx through aspartate-activated NMDA receptors made permeable by an accompanying alkaline shift in pHo caused by a fall in [lactate(-)]o. These insights have important clinical implications.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Aspartic Acid; Brain; Calcium; Disease Models, Animal; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Glycogen; Hydrogen-Ion Concentration; Hypoglycemia; Kynurenic Acid; Lactic Acid; Leukoencephalopathies; Mice; Mice, Inbred C57BL; Optic Nerve Injuries; Quinoxalines; Receptors, N-Methyl-D-Aspartate

The AMPA antagonist, NBQX, produced dose-dependent blockade of the locomotor stimulant effects of cocaine and methamphetamine in male, Swiss-Webster mice at doses which did not alter spontaneous locomotion. A similar finding was obtained with the competitive NMDA antagonist, NPC 12626, although blockade was only observed at the highest dose studied. The NMDA antagonists, (+)-HA-966 and 7-chlorokynurenic acid (7-CKA), which act at the strychnine-insensitive modulatory site of the NMDA receptor, only blocked the stimulatory effects of methamphetamine and with (+)-HA-966, blockade was only achieved at a dose that decreased spontaneous locomotor activity. These results provide evidence for the involvement of glutamatergic input in the control of behavior involving mesolimbic dopamine. Along with other findings these results suggest that glutamate receptors may be a target for the development of pharmacological therapies for the treatment of psychomotor stimulant abuse and for other disorders involving hyperfunction of the mesolimbic dopamine system (eg. schizophrenia).

Topics: Amino Acids; Animals; Cocaine; Excitatory Amino Acid Antagonists; Glutamic Acid; Kynurenic Acid; Male; Methamphetamine; Mice; Motor Activity; Pyrrolidinones; Quinoxalines