Background and Purpose: The aim of this study was to investigate the neurobehavioral consequences of focal ischemia in rats.Methods: We induced permanent occlusion of the left middle cerebral artery in 14 SpragueDawley rats, and used 13 sham-operated rats as controls. During surgery, brain temperature and body temperature were kept at normothermia. Neurobehavioral studies (neurological examination, passive avoidance task, Y maze test, and modified open-field test) were carried out 4 days after ischemia before killing the rats to evaluate histological damage.Results: Ischemia induced large infarcts in the cortex (138.6±8.5 mm

The pineal hormone melatonin has recently been shown to exert neuroprotective activity in a variety of experimental neuropathologies in which free radicals are involved. This neuroprotective effect has been attributed to the antioxidant properties of melatonin. Considering that free radicals also play a deleterious role in traumatic brain injury (TBI), the purpose of the present study was to determine whether melatonin would have a beneficial effect in this pathology. Head injury was induced in mice and the neurological deficit was evaluated at 24 hr by a grip test. In this model, the free radical scavenger, alpha-phenyl-tert-butyl-nitrone (2 x 100 mg/kg, i.p.) given 5 min and repeated at 4 hr after TBI was neuroprotective. Melatonin (1.25 mg/kg, i.p.) given 5 min and repeated at 1, 2, and 3 hr after head trauma also significantly reduced the neurological deficit. This beneficial effect was not due to melatonin-induced hypothermia since repeated treatment with melatonin did not modify the colonic temperature of mice. This study shows that melatonin exerts a beneficial effect on the neurological deficit induced by traumatic brain injury in mice. The mechanisms of this neuroprotection remains to be established, and more particularly, the contribution of the antioxidant activity of melatonin.

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1 The temporal changes in constitutive NO-synthase (cNOS) and in calcium-independent NO-synthase activities were studied in mice subjected to 2 h of transient focal cerebral ischaemia. The changes in brain nitrites/nitrates (NO x ) content were also studied. 2 NOS activities were measured by the conversion of L-[ 14 C]-arginine to L-[ 14 C]-citrulline. Brain NO x contents were investigated by the Griess colourimetric method. 3 cNOS activity in the infarcted cortical area was signi®cantly reduced after 6 h of reperfusion and this activity remained attenuated for up to 10 days after ischaemia. A calcium-independent NOS activity began to increase 48 h after reperfusion, reached a maximum at 7 days and returned to baseline at 10 days. 4 There was a signi®cant increase of brain NO x content beginning after 3 days of reperfusion. This increase was maximal at 7 days and returned to baseline at 10 days. 5 Thus, ischaemia followed by recirculation leads to a rapid, prolonged drop in cNOS activity in the infarcted cortex. There is also a substantial appearance of calcium-independent NOS activity in the later phase of transient ischaemia, leading to an important increase of NO x production.

The present study investigates the role of N-methyl-D-aspartate (NMDA) receptors in a model of transient focal cerebral ischemia in normotensive rats. The left middle cerebral artery and both common carotid arteries were occluded for 60 min. Preliminary studies indicated that this gave reproducible infarctions of the cortex and striatum. These infarctions were the result of severe ischemia followed by complete reperfusion after clamp removal, as showed by striatal tissue Po2 monitoring. Microdialysis indicated that glutamate concentration increased immediately after occlusion and returned to the baseline value 40 min after clamp removal. MK-801 (1 mg kg-1 i.v.), an antagonist of the NMDA glutamatergic receptor, reduced the cortical infarct volume by 29% (p < 0.001) and the striatal infarct volume by 14% (p < 0.05) when given just prior to ischemia, but had no neuroprotective activity when given 30 min after the onset of ischemia. This short therapeutic window for MK-801 suggests that NMDA receptors play only a transient role in reversible focal ischemia in rats.

1 In this study the e ect of the dose and administration time of N G -nitro-L-arginine methyl ester (L-NAME), an NO-synthase inhibitor, in a model of transient focal cerebral ischaemia in rats was investigated.2 Two injections of L-NAME were given, of 1, 3 and 10 mg kg 71 , 5 min and 3 h after the onset of ischaemia. None of the doses gave any striatal neuroprotection, but 1 and 3 mg kg 71 L-NAME reduced the infarcted volume in the cortex (by 26%, P50.01 for 1 mg kg 71 and 21%, P50.05 for 3 mg kg 71 ), whereas 10 mg kg 71 had no neuroprotective e ect. 3 Single injections of L-NAME 1 mg kg 71 , given 5 min or 3 h after ischaemia onset, had similar neuroprotective e ects on the cortical infarction as did the repeated injections. 4 L-NAME 1 mg kg 71 given 3, 6 or 9 h after ischaemia induction reduced the cortical infarct volume by 19% (P50.01) when given 3 h after ischaemia, by 21% (P50.01) when given at 6 h, and by 16% (P50.5) when given at 9 h, but had no neuroprotective activity when given 12 h after ischaemia. 5 Thus a low dose of L-NAME is neuroprotective in a model of transient focal ischaemia, with a wide therapeutic window, much larger than that found for MK-801.

This study investigates the effect of the NO synthase inhibitors, NG-nitro L-arginine methyl ester (L-NAME) and 7-nitro indazole (7-NI), on the neurological deficit 24 h after a moderate closed head injury in mice. Low doses of L-NAME or 7-NI given soon after the injury significantly reduced the neurological deficit compared to the vehicle-treated group. L-Arginine (300 mg/kg) did not alter the neurological deficit, but reversed the protective effects of both L-NAME and 7-NI when given at the same time. Both L-NAME and 7-NI had dose-related effects. The neuroprotective effects of L-NAME and 7-NI occurred when the drugs were given 5, 30, or 60 min after brain injury, but not when treatment was begun 2 h after brain injury, suggesting a short therapeutic window for both drugs. These results suggest that NO synthesis by neuronal NO synthase plays an important role in the early neurotoxic cascade leading to neurological deficit following traumatic brain injury.

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