nitroarginine and Epilepsy

Nitric oxide (NO) content in rat cerebral cortex was measured using Electron Spin Resonance (ESR) spectroscopy. A nearly fivefold elevation in NO content was found at the peak time of pentylenetetrazole (PTZ)-induced seizures. The administration of N-nitro-L-arginine (L-NNA), a competitive inhibitor of NO-synthase, at the dose of 250 mg/kg, completely prevented the NO increase induced by PTZ, although clonic convulsions in the animals have been observed. L-NNA (10 mg/kg) was shown to delay the onset of clonic seizures as well as to shorten the latency of the first convulsive twitch. The level of lipid peroxidation secondary products measured as the content of thiobarbituric acid reactive species (TBARS) was increased in the cerebral cortex of PTZ-treated rats. L-NNA (250 mg/kg) failed to prevent the increased TBARS level produced by PTZ. The results support the notion that NO may play a trigger role in the pathophysiology of convulsive seizures.

Topics: Animals; Arginine; Brain; Convulsants; Electron Spin Resonance Spectroscopy; Enzyme Inhibitors; Epilepsy; Lipid Peroxidation; Male; Nitric Oxide; Nitroarginine; Pentylenetetrazole; Rats; Rats, Wistar; Seizures

Using a nitric oxide (NO)-sensitive platinum microelectrode (SNM) modified with chitosan nickel (II) complex and Nafion (Nafion-CTS (Ni)-Pt), we observed the effect of nitric oxide synthase (NOS) inhibitor 7-nitro-indazole (7-NI) and N omega-nitro-L-arginine (L-NNA) on penicillin-treated hippocampal slices by simultaneously recording the stimulus-evoked field potentials and nitric oxide release from CA1 pyramidal neurons. Our results show: (1) The linear relationship range and detection limit of SNM were 4.5 x 10(-4)-1.0 x 10(-8) mol/L and 5.0 x 10(-8) mol/L respectively. (2) Penicillin (PEN) could elevate NO release, the number and amplitude of stimulus-evoked field potentials spike (SEPS) in concentration-dependent manner; (3) Both 7-NI and L-NNA depressed NO release and partly reversed the effect of penicillin. The above findings suggest that convulsant provoking effect of NO could be inhibited by NOS inhibitors. The NO-sensitive electrode may provide an useful tool for continuous detection of NO in biological tissues.

Topics: Animals; Anticonvulsants; Epilepsy; Evoked Potentials; Hippocampus; In Vitro Techniques; Indazoles; Microelectrodes; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Penicillin G; Rats

In the central nervous system, nitric oxide (NO) is increasingly being considered as a trans-synaptic retrograde messenger, being involved for instance in cellular responses to stimulation of glutamate receptors of the NMDA subtype. Thus, compounds that modify NO production, such as NO synthase inhibitors, may provide a means of altering NMDA receptor function. The functional consequences of NO synthase inhibition are, however, complicated by the fact that NO not only serves as a messenger to activate guanylyl cyclase and so to raise cGMP in target cells in response to NMDA receptor stimulation but also to induce feedback inhibition of the NMDA receptor via a redox modulatory site on the receptor complex. This may explain the contrasting results obtained previously with NO synthase inhibitors in animal models of ischaemia and seizures. In the present study, we tried to resolve the reported discrepancies about the effects of NO synthase inhibitors in seizure models by studying such drugs at various doses in a novel model of cortical seizure threshold. In this model, the threshold for seizures in rats is determined at short time intervals by applying ramp-shaped electrical pulse-trains directly to the cerebral cortex, allowing one to determine the time course of anti- or proconvulsant drug effects in individual rats. Two NO synthase inhibitors, NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester, were compared with a clinically effective antiepileptic drug, i.e. valproate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Analysis of Variance; Animals; Arginine; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Electrodes, Implanted; Epilepsy; Female; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Valproic Acid

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Calcium; Cells, Cultured; Cerebellar Cortex; Cyclic GMP; Electron Spin Resonance Spectroscopy; Enzyme Activation; Epilepsy; Feedback; Free Radicals; Glutamic Acid; Guanylate Cyclase; Kindling, Neurologic; Mice; Molsidomine; N-Methylaspartate; Nerve Tissue Proteins; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Receptors, N-Methyl-D-Aspartate

Cerebral evoked responses following direct electrical stimulation of the vagus and esophagus were compared in 8 epileptic subjects and with those recorded after esophageal stimulation in 12 healthy nonepileptic controls. Direct vagal stimulation was performed using a left cervical vagal pacemaker, which is used in the treatment of epilepsy. Esophageal stimulation was obtained with the use of an esophageal assembly incorporating two electrodes positioned 5 and 20 cm orad to the lower esophageal sphincter. Evoked potential responses were recorded with the use of 20 scalp electrodes. The evoked potential responses consisted of three distinct negative peaks and were similar with the use of either vagal or esophageal stimulation. The measured conduction velocity of the afferent response was 7.5 m/s in epileptic subjects and 10 m/s in healthy controls, suggesting that afferent conduction is through A delta-fibers rather than slower C afferent fibers. We conclude that the cortical-evoked potential responses following esophageal electrical stimulation are comparable to direct electrical stimulation of the vagus nerve and involve mostly A delta-fibers. This approach provides a method for the assessment of vagal afferent gastrointestinal sensory pathways in health and disease.

Topics: Adult; Arginine; Cerebral Cortex; Dose-Response Relationship, Drug; Electric Stimulation; Epilepsy; Esophagus; Evoked Potentials; Female; Humans; Male; Membrane Potentials; Middle Aged; Nitroarginine; Vagus Nerve

In response to NMDA receptor activation, hippocampal, striatal and cerebellar neurons synthesize nitric oxide (NO), which in turn elevates cGMP levels via guanylate cyclase. NO is increasingly being considered as a transsynaptic retrograde messenger, involved in neuronal plasticity. The effect of an inhibitor of NO synthase, L-NG-nitroarginine (NOArg), was studied on amygdala kindling and on kindled seizures in rats. NOArg increased kindling rate, particularly in its initial period, but did not modify seizure severity in previously kindled rats, although we have no definitive explanation for this effect. However, an enhanced post-synaptic excitability could be attributed to the blockade of the negative feed-back exerted by NO on the NMDA receptor.

Topics: Amino Acid Oxidoreductases; Amygdala; Animals; Arginine; Cyclic GMP; Epilepsy; Kindling, Neurologic; Male; Neuronal Plasticity; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley