Involvement of nitric oxide in kainic acid-induced excitotoxicity in rat brain.
The involvement of nitric oxide (NO) in kainic acid (KA)-induced excitotoxicity was studied in rat brain. With the onset of KA (15 mg kg(-1), s.c.)-induced seizures (convulsions) 30 min after injection, increases in NO, as measured by the formation of citrulline, were seen in cortex (302%), amygdala (171%) and hippocampus (203%). The highest increases were determined 90 min after onset of seizures (120 min after KA injection) with 633%, 314% and 365%, respectively. These changes in NO preceded significant decreases in ATP and phosphocreatine (PCr) ranging from 44 to 53% for ATP and from 40 to 52% for PCr in the respective brain areas. With the exception of the cortex, normal citrulline values were restored within 24 h. Pretreatment with the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN, 200 mg kg(-1), i.p.) or the antioxidant vitamin E (Vit-E, 100 mg kg(-1) per day for 3 days) prevented the increase in citrulline and significantly attenuated the loss in ATP and PCr without affecting seizure activity. It is concluded that seizures induced by KA produced a marked increase in the free radical NO, causing oxidative stress and leading to depletion of energy stores. The prevention of the increase in NO and preservation of ATP and PCr levels by PBN and Vit-E suggests the involvement of NO and other related free radicals, such as peroxynitrite (ONOO(-)). The lack of effect of PBN and Vit-E on seizure activity, suggests that NO is not involved in mechanisms regulating KA seizure generation and propagation. PBN and Vit-E or similar compounds may be important protective agents against status epilepticus-induced neuronal degeneration.
Milatovic
Dejan
D
Department of Pathology, Vanderbilt University, Nashville, TN, USA.
Gupta
Ramesh C
RC
Dettbarn
Wolf D
WD
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002956:Citrulline / Q000096:biosynthesis; D003497:Cyclic N-Oxides; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014810:Vitamin E / Q000494:pharmacology
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D014810:Vitamin E; D002956:Citrulline; D009569:Nitric Oxide; C029217:phenyl-N-tert-butylnitrone; D000255:Adenosine Triphosphate; D007608:Kainic Acid