Phenytoin-induced glutathione depletion in rat peripheral nerve.
Administration of high doses (150-250 mg/kg body weight) of phenytoin (DPH) promote a 40% decrease in glutathione (GSH) content of rat sciatic nerve. This DPH-induced GSH depletion is accompanied with an electrophysiological impairment of peripheral neuromuscular function. H7 (20 mg/kg body weight IP, 30 min prior to DPH), a protein kinase C inhibitor, was able to prevent the DPH-induced GSH depletion only at the lower DPH dose used. This same inhibitor completely prevented the electrophysiological impairment at the lower DPH dose, and only partially at the higher DPH dose used. These results confirm the hypothesis of a DPH-dependent activation of PKC (that might be triggered by, or be the consequence of, the reduction of the intracellular antioxidant GSH), as one of the pathophysiological mechanisms involved in DPH-induced neurotoxicity.
Department of Physiology, University of Valencia, Spain.
A
A
Raya
J
J
Gallego
F
F
Bosch-Morell
J
J
Romá
F J
FJ
Romero
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D010672:Phenytoin / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D010879:Piperazines; D010672:Phenytoin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D005978:Glutathione