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Prevention of kainic acid seizures-induced changes in levels of nitric oxide and high-energy phosphates by 7-nitroindazole in rat brain regions.

Abstract：

:Previous studies using the spin trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) and the antioxidant vitamin E established the involvement of free radicals in kainic acid (KA)-induced neurotoxicity. In the present study, we examined the effects of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI) to establish a possible role of nitric oxide (NO) in the neurotoxicity caused by KA-induced status epilepticus (SE). A single injection of KA (15 mg/kg, s.c.) induced seizures within 40-45 min, progressing to full seizure activity lasting about 3 h. Following microwave (head-focused) irradiation, perchloric acid extracts of rat brain regions (cortex, amygdala, and hippocampus) were analyzed for citrulline (determinant of NO) and high-energy phosphates (HEP) and their metabolites using high-performance liquid chromatograph (HPLC). KA-induced seizures produced a maximum increase in NO (3- to 6-fold) and a decrease in HEP (ATP 45-51% and phosphocreatine 45-58%) 2 h after KA injection in brain regions tested. 7-NI (50 mg/kg, i.p.) when given alone, reduced citrulline/NO levels (10-24%), while repeat administration of 7-NI (60 min apart) reduced NO levels by 32-49%. Neither application of 7-NI produced changes in HEP levels or toxicity. Pretreatment with 7-NI 30 min before KA injection, delayed the onset of seizures by 15-20 min, and significantly prevented an increase in NO and a decrease in HEP. Repeat administration of 7-NI, i.e. 30 min before and 30 min after KA injection, further increased protection by the delayed onset of seizures, attenuating the increase in NO and the decrease in HEP. Neurotoxicity of seizures involves activation of nNOS and of energy consumption in affected neurons. This increased energy consumption, coupled with decreased energy production caused by NO-induced mitochondrial dysfunction, may be a contributing factor to neuronal injury in KA toxicity.

journal_name

Brain Res

journal_title

Brain research

authors

Gupta RC,Dettbarn WD

doi

10.1016/s0006-8993(03)03034-8

subject

Has Abstract

pub_date

2003-08-15 00:00:00

pages

184-92

issue

1-2

eissn

0006-8993

issn

1872-6240

pii

S0006899303030348

journal_volume

981

pub_type

杂志文章

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Prevention of kainic acid seizures-induced changes in levels of nitric oxide and high-energy phosphates by 7-nitroindazole in rat brain regions.