title: Role of the NMDA receptor and iron on free radical production and brain damage following transient middle cerebral artery occlusion.
abstract: Excess activation of ionotropic glutamate receptors and iron is believed to contribute to free radical production and neuronal death following hypoxic ischemia. We examined the possibility that both NMDA receptor activation and iron overload determine spatial and temporal patterns of free radical production after transient middle cerebral artery occlusion (tMCAO) in male Sprague-Dawley rats. Mitochondrial free radical (MFR) levels were maximally increased in neurons in the core at 1 h and 24 h after tMCAO. Early MFR production was blocked by administration of MK-801, an NMDA receptor antagonist, but not deferoxamine, an iron chelator. Neither MK-801 nor deferoxamine attenuated late MFR production in the core. Increased MFRs were observed in penumbral neurons within 6 h and gradually increased over 24 h after tMCAO. Slowly-evolving MFRs in the core and penumbra were accompanied by iron overload. Deferoxamine blocked iron overload but reduced MFR production only in the penumbra. Combined MK-801/deferoxamine reduced late MFR production in both core and penumbra in an additive manner. Combination therapy significantly ameliorated infarction compared with monotherapy. These findings suggest that the NMDA receptor activation and iron overload mediate late MFR production and infarction after tMCAO.
authors.affiliation: GNT Pharma Research Institute, Gomae-Dong 381-1, Giheung-Gu, Yongin-Si, 446-901, South Korea.
authors.forename: Doo Soon
authors.initials: DS
authors.lastname: Im
authors.forename: Jeong Wook
authors.initials: JW
authors.lastname: Jeon
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.forename: Sung Ig
authors.initials: SI
authors.lastname: Cho
authors.forename: Yong Beom
authors.initials: YB
authors.lastname: Lee
authors.forename: Byoung Joo
authors.initials: BJ
authors.lastname: Gwag
mesh_terms: D000818:Animals; D001925:Brain Damage, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007501:Iron / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D005609:Free Radicals; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D007501:Iron; D003676:Deferoxamine