In rats, we established global ischemia for 30 min by ligating both common carotid arteries and by hypotension that was induced by drawing blood from tail vein. Reoxygenation has been provided for 1 h by deligating the common carotid arteries. In the treatment group, lamotrigine (20 mg/kg) has been applied intraper-itoneally just after the ischemic insult; then ischemia and reperfusion periods were followed as in ischemia or reperfusion groups similarly. In sham-operated animals, common carotid arteries were exposed but not ligated. NO indicators nitrite and nitrate were found to be increased in cortical, subcortical, and cerebellar brain regions after ischemia. This increase persisted and continued during reperfusion. Although NO indicators were found to be decreased in the lamotrigine-treated group, they were still higher than levels in the ischemic group (122) (Fig. 8).
Similar results have been reported by different groups. NOS activity is transiently activated during global cerebral ischemia produced by occlusion of both common carotid arteries together with induced hypotension in rats (123). In complete global ischemia, NO concentration was reported to increase transiently at 2.5 min and decreased thereafter. The NOS inhibitor NG-nitro-l-argi-nine abolished NO elevation during ischemia (124). During exposure to global ischemia for 7 min, the generation of NO increased in all parts of the brain. In the hippocampus the rate of NO formation during ischemia increased by sixfold from a control rate. This increase was attenuated 47% by treatment with the NOS antagonist 7-nitroindazole (7-NI) (125). Brain ischemia induced by ligation of both common carotid arteries in gerbils increased significantly NOS activities as well as the level of cGMP. The ischemia evoked changes of NOS/cGMP were eliminated by a specific inhibitor of the neuronal form of NOS, 7-NI. The inhibitor of guanylate cyclase, LY-83583, administered before ischemia diminished not only the enhanced level of cGMP but also NOS activity stimulated by ischemia (126). 7-NI was shown to be neuroprotective in 20-min global ischemia in rats, suggesting that NO released from neurons in ischemic conditions has a deleterious influence on hippocampal pyramidal neurons (127,128). Bilateral carotid artery occlusion and combined vertebral artery occlusion in rats produced a transient increase in hippocampal NO2 and NO3 levels, according to the duration and degree of ischemic insults which was abolished by an inducible NOS inhibitor aminoguanidine (129). Cerebral ischemia produced by bilateral occlusion of the common carotid arteries (30 min) followed by 4 h of reperfusion resulted in a significant increase in total and inducible NOS activity and a significant increase in the production of NO and superoxide in the cerebral hemispheres (130). TGF-P1 in a low dose range was shown to have the capacity to reduce injury to CA1 hippocampal neurons caused by transient global ischemia in rats (111). Cerebral global transient ischemia induced by bilateral clamping of the carotids for 30 min and reduction of arterial pressure to 50-60 mm Hg caused a rise in cNOS activity and cGMP levels. Pretreatment with desmethyltirilazad (21-aminoste-roid) or dizocilpine maleate (NMDA receptor antagonist) or nimodipine (calcium channel antagonist) individually or in combination of three drugs significantly suppressed the increase in cNOS activity and cGMP levels (131-133). It was reported that pretreatment with Radix salviae miltiorrhizae (RSM) reduced the
increased cerebral NO concentration on reperfusion in a four-vessel occlusion rat model after 30 min of global ischemia and 15 min of reperfusion (134). It was demonstrated that hypothermia suppresses the elevation in intrajugular NO after cerebral ischemia-reperfusion (135). Exogenous melatonin administration prevented the increases in cerebral cortical and cerebellar NO production (nitrite/ nitrate levels and cGMP) after transient bilateral carotid artery occlusion/reperfusion in adult Mongolian gerbils (136).
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