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Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system and initiates the events leading to ischemic brain damage. Glutamate receptor antagonists are being used to reduce neuronal damage observed after hypoxia and ischemia. The glutamate receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine maleate (MK-801) crosses the blood-brain barrier readily and produces a non-competitive use-dependent blockade of the N-methyl-D-aspartate subtype of glutamate receptor. The aim of this study was to investigate effects of MK-801 administered before and just after the onset of ischemia in rats on nitrite and cyclic guanosine monophosphate (cGMP) levels. Focal cerebral ischemia in rats was produced by permanent occlusion of right middle cerebral artery (MCAO). Nitrite and cGMP levels were measured in both cortex and cerebellum at 0, 10, and 60 min following MCAO. The same parameters were measured in rats treated with MK-801 (0.5 mg/kg, i.p.) 30 min before or just after MCAO. Ipsilateral cortical nitrite levels were increased relative to contralateral cortex after MCAO. No significant changes were observed in cerebellum. The cGMP concentrations in both sides of the cortex and cerebellum were increased at 10 and 60 min compared with 0 min values. cGMP level in the ipsilateral cortex was higher than contralateral cortex, whereas the opposite was found for the cerebellum. MK-801 treatment before or just after MCAO decreased significantly nitrite and cGMP production. Our data indicate that MK-801 treatment before or just after focal ischemia prevents the increase in NO and cGMP production.

The neuroprotective efficacies of citicoline and lamotrigine, alone and in combination, were investigated in experimental permanent focal ischemia. Seven groups of adult male rats underwent focal cerebral ischemia and were given the following treatments: placebo (P), low and high doses of citicoline (C250 and C500, 250 and 500 mg/kg/day i.p., respectively), low and high doses of lamotrigine (L50 and L100, 50 and 100 mg/kg/day p.o., respectively), and combination regimes of both drugs in low (C250 + L50) and high doses (C500 + L100). Citicoline, but not lamotrigine, exerted neuroprotective efficacy during this acute ischemic stroke model. The citicoline and lamotrigine combination did not provide a significant additive neuroprotective effect.

The effect of MK-801 on ischemic neuronal damage was studied in a rat model of permanent focal cerebral ischemia in terms of ipsilateral and contralateral cortical and cerebellar tissue lipid peroxides. Forty-five male Swiss Albino rats were assigned into one of four groups: sham operated as controls, subjected to right middle cerebral artery occlusion (MCAO) or injection of MK-801 (0.5 mg/kg i.p.) either 30 min before or just after right MCAO. Changes in lipid peroxides were expressed as nmol malondialdehyde (MDA) and conjugated diene (CD)/mg protein. MDA values after 60 min of ischemia relative to contralateral cortex and CD levels in 0, 10 and 60 min after ischemia were found to be higher in ipsilateral cortex than those in contralateral cortex. On the other hand, contralateral cerebellar MDA levels in 0 and 60 min of ischemia and CD levels in 0, 10 and 60 min after ischemia were found to be higher than those in ipsilateral cerebellum. Pharmacological inhibition of glutamate receptor by MK-801 before or just after permanent MCAO decreased significantly the MDA and CD levels in both cortex and cerebellum. Although no significant differences found in MDA values between rats pre- and posttreated with MK-801, CD levels in posttreated group seemed significantly lower than those in pretreated group. On the whole, these results suggest that MDA and CD represent early biochemical marker of lipid peroxidation in ischemic tissues, reflecting the radical-mediated tissue damage.

The effects of Lamotrigine (LTG) which blocks ischemia induced glutamate (Glu) release, on lipid peroxidation have been evaluated in cortical and cerebellar tissues of rat brain during focal cerebral ischemia. A total of 45 rats were randomly assigned into one of four groups; sham operated animals as controls, animals subjected to middle cerebral artery occlusion (MCAO) and treatment groups with LTG (20 mg/kg i.p.) either 30 min before or just after MCAO. Changes in lipid peroxides were expressed as nanomoles of malondialdehyde (MDA) and conjugated diene (CD) per milligram of protein. MDA values following 60 min of ischemia relative to contralateral cortex and CD levels in 0, 10 and 60 min of ischemia were found to be higher in the ipsilateral cortex than those in the contralateral cortex. On the other hand, contralateral cerebellar MDA levels after 0 and 60 min of ischemia and CD levels after 0, 10 and 60 min of ischemia were higher than those in the ipsilateral cerebellum. Pharmacological inhibition of Glu release significantly decreased the MDA and CD production in both cortex and cerebellum. Pre- or post-ischemic administration of LTG did not significantly change CD levels, but MDA levels in contralateral cortex were found to be significantly decreased than those in ischemic cortex in both pre- and post-treated group.

The effect of N omega-nitro-L-arginine methyl ester (L-NAME) on ischemic neuronal damage was studied in a rat model of permanent focal cerebral ischemia in terms of ipsilateral and contralateral cortical and cerebellar tissue lipid peroxides. Forty-five male Swiss Albino rats were assigned to one of four groups; sham operated as control, subjected to right middle cerebral artery occlusion or injection of L-NAME (10 mg/kg i.p.) either 30 min before or just after right middle cerebral artery occlusion. Changes in lipid peroxides were expressed as nanomoles of malondialdehyde and conjugated diene per milligram of protein. Malondialdehyde values following 60 min of ischemia relative to contralateral cortex and conjugated diene levels in 0, 10 and 60 min of ischemia were found to be higher in ipsilateral cortex than in contralateral cortex. On the other hand, contralateral cerebellar malondialdehyde levels after 0 and 60 min of ischemia and conjugated diene levels after 0, 10 and 60 min of ischemia were higher than those in ipsilateral cerebellum. Pharmacological inhibition of nitric oxide synthase by L-NAME before or just after permanent middle cerebral artery occlusion significantly decreased the malondialdehyde and conjugated diene levels in both the cortex and the cerebellum. No significant differences were found in malondialdehyde values between rats that had been pre- and post-treated with L-NAME, but conjugated diene levels in the post-treated group seemed to be significantly lower than those in the pretreated group. On the whole, these results suggest that malondialdehyde and conjugated diene represent early biochemical markers of lipid peroxidation in ischemic tissues, reflecting the radical-mediated tissue damage.

Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2, 4-triazine) is an anticonvulsant drug that blocks voltage-gated sodium channels and inhibits the ischemia-induced release of glutamate. Experiments in primary neuronal cultures implicate nitric oxide (NO) as a mediator of glutamatergic neurotoxicity acting via N-Methyl-D-Aspartate (NMDA) receptors. The effect of glutamate release inhibitor, Lamotrigine upon NO and cGMP production has been examined in focal cerebral ischemia in rats. Focal cerebral ischemia was produced by the permanent occlusion of right middle cerebral artery (MCA) in urethane anesthetized rats. A number of indicators of brain NO production (nitrite, cGMP) were determined in ipsilateral and contralateral cerebral cortex and cerebellum after 0, 10, 60 min of focal cerebral ischemia. The same parameters were measured in rats treated with Lamotrigine (20 mg/kg, i.p.) 30 min before or just after the occlusion of the right MCA.

Recent evidence in primary neuronal cell culture implicates NO as a mediator of glutamatergic neurotoxicity acting via N-methyl-D-aspartate (NMDA) receptors. In this study, we investigated the effects of inhibition of NOsynthase activity in focal cerebral ischemia in rats. Focal cerebral ischemia was produced by permanent occlusion of right MCA in urethane anesthetized rats. A number of indicators of brain NO production, nitrite and cGMP were determined in ipsilateral and contralateral cerebral cortex and cerebellum after 0, 10 and 60 minutes of focal cerebral ischemia. The same parameters were measured in rats pre- and posttreated with the potent Nitric oxide synthase (NOS) inhibitor, NW-nitro-L-arginine methyl ester (L-NAME).