ascorbic-acid and pyrrolidine-2-4-dicarboxylic-acid

The effect of diethylmaleate administration on ascorbic acid release following cerebral ischemia was investigated in anesthetized rat brain cortex. Cerebral ischemia, induced by ligating bilateral common carotid arteries and unilateral middle cerebral artery, significantly increased the extracellular ascorbic acid levels. Diethylmaleate (4 mmoles/kg, i.p.), which has been shown in earlier studies to decrease the ischemia-induced glutamate release, significantly reduced the ischemia-induced ascorbic acid release. The ischemia-induced ascorbic acid release was unaffected by perfusing NMDA receptor antagonist MK 801 (75 microM). Additionally, elevated extracellular glutamate levels, achieved by either externally applied glutamate solutions or by perfusing L-trans-pyrrolidine-2,4-dicarboxylate (PDC) (31.4 mM and 15.7 mM) to inhibit the glutamate uptake transporter, also significantly increased the extracellular ascorbic acid levels. These results suggested that ascorbic acid release in cerebral ischemia might be related to the elevated extracellular glutamate levels, which occurs following cerebral ischemia.

Topics: Amino Acid Transport System X-AG; Anesthesia; Animals; Ascorbic Acid; Brain Chemistry; Brain Ischemia; Carrier Proteins; Cerebral Cortex; Dicarboxylic Acids; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Extracellular Space; Glutamate Plasma Membrane Transport Proteins; Glutamic Acid; Glutathione; Infarction, Middle Cerebral Artery; Male; Maleates; Microdialysis; Neurotransmitter Uptake Inhibitors; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Symporters

1. The present study concerns the possible relationship between glutamate excitotoxicity and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+) neurotoxicity on striatal dopaminergic terminals. 2. MPP+ neurotoxicity has been studied by means of two MPP+ perfusions separated by 24 h. After the second MPP+ 1 mM perfusion, dopamine extracellular output, measured by microdialysis, was considered to be an index of the dopaminergic neurone damage produced by the first MPP+ 1 mM perfusion. 3. High concentration (10 mM) of glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) stimulated basal release of dopamine and protected against the neurotoxic effect of MPP+. 4. PDC 10 mM perfusion produced an increase in the extracellular output of glutamate and aspartate, and a decrease in that of ascorbate. 5. The protective effect against MPP+ toxicity observed with PDC 10 mM was completely abolished when this glutamate uptake inhibitor was co-perfused with ascorbate 0.5 mM. 6. These results suggest that glutamate-induced neurotoxicity is not involved in MPP+ toxicity. The protective effect found with the glutamate uptake inhibitor could be due to a decrease in extracellular ascorbate levels.

Topics: 1-Methyl-4-phenylpyridinium; Amino Acids, Essential; Animals; Ascorbic Acid; Aspartic Acid; Dicarboxylic Acids; Dopamine; Dopamine Agents; Extracellular Space; Glutamic Acid; Immunohistochemistry; Male; Microdialysis; MPTP Poisoning; Neostriatum; Nerve Endings; Neurotransmitter Uptake Inhibitors; Pyrrolidines; Rats; Rats, Wistar; Tyrosine 3-Monooxygenase

It was found that systemic application of ethanol induced brain ascorbate (AA) release. In order to study the mechanism of ethanol-evoked AA release, the role of brain glutamatergic neurotransmission was investigated using in vivo voltammetry in the striatum of freely moving rats. Pretreatment with L-trans-pyrrolidine-2,4-dicarboxylate (PDC, 10 nmol, i.c.v.), a glutamate (Glu) uptake blocker, potentiated ethanol (1 g/kg, intraperitoneal injection, i.p.)-evoked release of brain AA. N-methyl-D-aspartate (NMDA, 1 nmol, i.c.v.) produced a fast transient increase in extracellular AA, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, 1 nmol, i.c.v.) produced a decrease in extracellular AA (75.8 +/- 3% of control). Kainate (KA, 1 nmol, i.c.v.) produced an initial decrease (48.7 +/- 11.7% of control) then an increase (250 +/- 68.5% of control) in extracellular AA. These results suggest that systemic administration of ethanol may affect the release or uptake of brain glutamatergic neurotransmitters which appear to regulate brain AA release. The NMDA, but not the non-NMDA, type of Glu receptor may be responsible for this regulation.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Ascorbic Acid; Brain Chemistry; Dicarboxylic Acids; Electrophysiology; Ethanol; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Injections, Intraventricular; Kainic Acid; Male; Microelectrodes; N-Methylaspartate; Neostriatum; Piperazines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

Extracellular brain ascorbate fluctuates with neuronal activity. There is previous evidence that the release of ascorbate is triggered by the re-uptake of neuronally released glutamate. This hypothesis predicts that drugs which block the release and re-uptake of glutamate will also block the release of ascorbate. In the present experiments we have used a novel dialysis electrode which allows continuous monitoring of physiologically induced ascorbate release from the striatum in freely moving rats. An infusion of the enzyme ascorbic acid oxidase abolished the increase in oxidation current in response to tail-pinch, which identified it as an ascorbate current. Perfusion with tetrodotoxin reduced the response to 25% and with CdCl2 to 4% of control. Perfusion with the uptake blocker L-trans-pyrrolidine-2,4-di-carboxylate reduced the response to 24% of control. A neuroprotective function for this coupling of ascorbate and glutamate release is discussed.

Topics: Animals; Ascorbate Oxidase; Ascorbic Acid; Brain; Cadmium; Calcium; Dicarboxylic Acids; Excitatory Amino Acid Antagonists; Glutamates; Male; Physical Stimulation; Pyrrolidines; Rats; Rats, Sprague-Dawley; Tetrodotoxin