Summary:The effects of the glutamate N-methyl-D aspartate (NMDA) receptor antagonist, MK-801, upon ischemic brain damage has been examined in anesthe tized cats. Focal cerebral ischemia was produced by per manent occlusion of one middle cerebral artery and the animals were killed 6 h later. The amount of early isch emic damage was assessed in coronal sections at 16 pre determined stereotactic planes. Pretreatment with MK-801 (5 mg/kg, i.v.). 30 min before occlusion of the Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system. The ac tions of glutamate are mediated via three pharma cologically distinct subtypes of receptor, the no menclature of which reflects the preferred agonist at each receptor subtype viz. the quisqualate-, kainate-, and N-methyl-D-aspartate-(NMDA)-pre ferring receptor (Greenamyre et aL, 1985). Gluta mate has recently been implicated in the patho physiology of cerebral ischemia (Meldrum 1985; Rothman and Olney, 1986). Glutamate itself is neu rotoxic when injected into cerebral tissue (Rothman and Olney, 1986). Cerebral ischemia is associated with a massive increase in extracellular glutamate concentrations (Benveniste et aL, 1984;Hagberg et aL, 1985). Destruction of glutamatergic afferent pathways or intracerebral administration of NMDA receptor antagonists can reduce the early ischemic damage to the hippocampus in cerebral ischemia and the neuronal necrosis which is observed sev eral days after a period of cerebral ischemia or se-
Recent arouse of interest indicated that drug resistant proteins are markedly over-expressed in the epileptogenic tissue and they may be responsible for the one-third of the epileptic patients who were refractory to anti-epileptic drugs (AEDs). Since several AEDs may act as substrates for these drug resistant proteins, the enhanced function of such proteins may increase drug extrusion, resulting in inadequate response to drug therapy in patients with epilepsy. We studied expression of the multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1) in the epileptic tissues resected surgically in 28 patients with focal cortical dysplasia (FCD) by immunohistochemistry. The results were compared with 10 normal necropsy brain tissues. Normal brain showed no MDR1 expression in neurons and astrocytes, while MRP1 expression was very weak, which were encountered in a few samples. MDR1 expression was mainly localized on the vascular endothelial cells. In contrast to normal brain, we found intense MDR1 and MRP1 expression in both neurons and reactive astrocytes in the vast majority of dysplastic tissues. The majority of the dysplastic neurons demonstrated moderate to strong MRP1 immunoreactivity. Endothelial cells showed both MDR1 and MRP1 expression in the majority of the specimens studied. Multidrug transporters are over-expressed in the epileptogenic zone in patients with FCD. These results are concordant with previous studies, in which over-expression of multidrug proteins were shown in epileptogenic brain tissue in patients with FCD, that the over-expression of drug transport proteins in tissue from patients with refractory epilepsy may explain one possible mechanism for drug resistant in these pathologies.
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