研究者詳細 - 堀口　崇

論文 - 堀口　崇

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虚血後から開始した低脳温はラット一過性前脳虚血後に生じるヒドロキシラジカルの産生を抑制する

堀口　崇

脳卒中 26 498 - 502 2004年

研究論文（学術雑誌）, 単著

脳圧制御困難な重症頭部外傷における低体温両方の適応ー特に年齢と治療成績の観点からー

斉藤良一、堀口　崇、稲桝丈司、三島　牧、真柳圭太、黒島義明、中村芳樹市来嵜　潔

神経外傷 27 90 - 94 2004年

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"Occult" ruptured cerebral aneurysms revealed by repeat angiography

Inamasu Joji, Nakamura Yoshiki, Saito Ryoichi, Horiguchi Takashi, Kuroshima Yoshiaki, Mayanagi Keita, Orii Maaya, Ichikizaki Kiyoshi

Clinical Neurology and Neurosurgery 106 （ 1 ） 33 - 37 2003年12月

ISSN 0303-8467

Not infrequently, cerebral angiography performed immediately after the onset of subarachnoid hemorrhage (SAH) fails to reveal any causative lesion. Although the cause of the SAH in most of these cases remains unknown, repeat angiography sometimes discloses a lesion not detected by the initial angiography. The frequency of finding a ruptured aneurysm by repeat angiography and the angiographic characteristics of such aneurysms have been investigated retrospectively. Nineteen among 316 non-traumatic SAH patients (6%) showed initially negative angiogram, and 7 of 19 patients (36%) were identified as harboring an "initially occult" aneurysm. It was possible to identify the expected cause of these initial false-negative angiograms in four of those seven patients. The aneurysm was located in the anterior communicating artery (ACoA) complex in four of the seven patients. When interpreting the angiograms of patients with SAH, neurologists and neurosurgeons should bear in mind the finding that the ACoA complex is the most frequent site of "initially occult" aneurysms. One patient had a dissecting aneurysm of the internal carotid artery, and although such lesions have been considered rare, they should be included in the differential diagnosis of SAH of unknown origin. © 2003 Elsevier B.V. All rights reserved.

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Diazoxide induces delayed pre-conditioning in cultured rat cortical neurons

Kis Bela, Rajapakse Nishadi C., Snipes James A., Nagy Krisztina, Horiguchi Takashi, Busija David W.

Journal of Neurochemistry 87 （ 4 ） 969 - 980 2003年11月

ISSN 0022-3042

We investigated the effect of diazoxide on neuronal survival in primary cultures of rat cortical neurons against oxygen-glucose deprivation (OGD). Diazoxide pre-treatment induced delayed pre-conditioning and almost entirely attenuated the OGD-induced neuronal death. Diazoxide inhibited succinate dehydrogenase and induced mitochondrial depolarization, free radical production and protein kinase C activation. The putative mitochondrial ATP-sensitive potassium channel blocker 5-hydroxydecanoate abolished the protective effect of diazoxide while the non-selective K_ATP channel blocker glibenclamide did not. The non-selective K_ATP channel openers nicorandil and cromakalim did not improve viability. Superoxide dismutase mimetic, M40401, or protein kinase C inhibitor, chelerythrine, prevented the neuroprotective effect of diazoxide. Diazoxide did not increase reduced glutathione and manganese-superoxide dismutase levels but we found significantly higher reduced glutathione levels in diazoxide-pre-conditioned neurons after OGD. In pre-conditioned neurons free radical production was reduced upon glutamate stimulation. The succinate dehydrogenase inhibitor 3-nitropropionic acid also induced pre-conditioning and free radical production in neurons. Here, we provide the first evidence that diazoxide induces delayed pre-conditioning in neurons via acute generation of superoxide anion and activation of protein kinases and subsequent attenuation of oxidant stress following OGD. The succinate dehydrogenase-inhibiting effect of diazoxide is more likely to be involved in this neuroprotection than the opening of mitochondrial ATP-sensitive potassium channels.

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Neuroprotection against hypoxia-ischemia in neonatal rat brain by novel superoxide dismutase mimetics

Shimizu Katsuyoshi, Rajapakse Nishadi, Horiguchi Takashi, Payne R. Mark, Busija David W.

Neuroscience Letters 346 （ 1-2 ） 41 - 44 2003年07月

ISSN 0304-3940

We investigated the effects of two new low molecular weight nonpeptidyl superoxide dismutase (SOD) mimetics (M40403/M40401; MetaPhore Pharmaceuticals) on infarct volume after hypoxia-ischemia injury (H/I) in immature rats. Animals received vehicle or different doses of M40403 or M40401 i.p. 2 h before exposure to 3 h of 8% hypoxia. The infarct volume of the hemisphere ipsilateral to carotid ligation 24 h later was 73.9±8.9% in vehicle animals (n=9), and decreased to 39.7±7.2% (P<0.05, n=10) in animals treated with 3 mg/kg M40403 and to 37.2±6.4% for animals receiving 3 mg/kg M40401 (P<0.05, n=8). These data indicate that the SOD mimetics M40403 and M40401 have protective effects against hypoxic-ischemic brain injury, and suggest the involvement of superoxide anion in neuronal cell injury during H/I. © 2003 Elsevier Science Ireland Ltd. All rights reserved.

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Diazoxide pretreatment induces delayed preconditioning in astrocytes against oxygen glucose deprivation and hydrogen peroxide-induced toxicity

Rajapakse Nishadi, Kis Bela, Horiguchi Takashi, Snipes James, Busija David

Journal of Neuroscience Research 73 （ 2 ） 206 - 214 2003年07月

ISSN 0360-4012

Recent studies suggest that activation of mitochondrial ATP-sensitive potassium channels (mK_ATP) with diazoxide can protect neurons against ischemic stress. However, it is not yet known whether astrocytes, which are more resilient against ischemia, respond similarly to diazoxide. We exposed cultured astrocytes to oxygen-glucose deprivation (OGD) or hydrogen peroxide (H₂O₂) with or without pretreatment with the mK_ATP opener diazoxide. Marked decreases in astrocyte viability were evident after 9 and 12 hr of OGD [76% ± 3% (n = 50) and 60% ± 1% (n = 50)] and 400 and 600 μM H₂O₂ [40% ± 2% (n = 16) and 25% ± 2% (n = 16)], respectively, compared with no treatment (100% ± 1%). Diazoxide treatment (3 days of sequential application) dramatically reversed the negative effects of OGD and H₂O₂, resulting in complete blockade of astrocyte cell death. Effects of diazoxide were blocked by the mK_ATP blocker 5-hydroxydecanoic acid (5-HD). Furthermore, incubation of astrocytes with diazoxide resulted in loss of mitochondrial membrane potential monitored by tetramethylrhodamineethylester fluorescence. Additionally, generation of reactive oxygen species was observed in response to diazoxide, assessed using the oxidation-sensitive dye hydroethidine, and this effect was abolished by antioxidants, catalase, and a superoxide dismutase mimetic, M40401. Finally, diazoxide increased the protein level of phosphorylated protein kinase C (PKC) revealed by immunoblot analysis. Our findings demonstrate that opening of mK_ATP by diazoxide identifies a delayed preconditioning effect that is protective against two types of injury in astrocytes and that diazoxide may deliver protection via mitochondrial depolarization, free radical production, and PKC activation. © 2003 Wiley-Liss, Inc.

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Effect of intra-ischemic hypothermia on the expression of c-Fos and c-Jun, and DNA binding activity of AP-1 after focal cerebral ischemia in rat brain

Akaji Kazunori, Suga Sadao, Fujino Tadahiro, Mayanagi Keita, Inamasu Joji, Horiguchi Takashi, Sato Shuzo, Kawase Takeshi

Brain Research 975 （ 1-2 ） 149 - 157 2003年06月

ISSN 0006-8993

It is unknown whether immediate early gene (IEG) induction and subsequent late gene regulation after ischemia is beneficial or deleterious. The aim of this study was to examine the effect of hypothermia on expression of c-Fos and c-Jun, and AP-1 DNA binding activity, after transient focal cerebral ischemia in rat brain, and clarify the role of IEGs and AP-1 after insults. Male Wistar rats underwent right middle cerebral artery occlusion for 1 h with the intraluminal suture method. During ischemia, animals were assigned to either normothermic (NT) or hypothermic (HT) groups. In the NT group, brain temperature was observed to spontaneously increase to 40°C during ischemia. In the HT group, brain temperature decreased to 30°C. Infarct volume in cortex was decreased in the HT group, compared with that in the NT group (P<0.001). Increased c-Fos immunoreactivity in the cortex was observed at 3 h after reperfusion in the HT, but not the NT group, while c-Jun expression was not affected by HT treatment. There was also a significant increase in AP-1 DNA binding activity at 3 h in the HT group when compared to the NT group (P<0.01). In conclusion, hypothermia decreased cerebral infarction in association with early increases in c-Fos expression and AP-1 DNA binding activity in peri-infarct cortex. It remains to be established whether such responses are a cause or consequence of cell survival, but these results clearly establish that altered transcription is a key feature of tissue spared following hypothermic focal ischemia. © 2003 Elsevier Science B.V. All rights reserved.

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Postischemic hypothermia inhibits the generation of hydroxyl radical following transient forebrain ischemia in rats

Horiguchi Takashi, Shimizu Katsuyoshi, Ogino Masahiro, Suga Sadao, Inamasu Joji, Kawase Takeshi

Journal of Neurotrauma 20 （ 5 ） 511 - 520 2003年05月

ISSN 0897-7151

A small reduction of body temperature during reperfusion following cerebral ischemia has been known to ameliorate neuronal injury. However, the mechanisms underlying postischemic hypothermia-induced neuroprotection are poorly understood. The burst of reactive oxygen species (ROS) formation that occurs during reperfusion has been documented to be involved in ischemic neuronal degeneration. In this study, we investigated the effect of postischemic hypothermia on ROS production following transient forebrain ischemia using an in vivo microdialysis technique. Forebrain ischemia was induced by bilateral carotid artery occlusion combined with hemorrhagic hypotension for 20 min in male Wistar rats. The body temperature was kept at 37°C during ischemia and controlled at either 32°C or 37°C after reperfusion. The amount of hydroxyl radical produced in striatum was evaluated by measurement of 2,3- and 2,5-dihydroxybenzoic acid (DHBA), which is generated by salicylate hydroxylation. We also measured the extracellular concentration of xanthine, while determining striatal blood flow by the hydrogen clearance technique. In animals whose postischemic body temperature was maintained at 37°C, the levels of 2,3- and 2,5-DHBA significantly increased after reperfusion. The peak levels of 2,3- and 2,5- DHBA were 2.9-fold and 2.7-fold increased above the corresponding baseline values, respectively. Postischemic hypothermia completely inhibited the hydroxyl radical formation. Likewise, xanthine formation was also inhibited by postischemic hypothermia. In contrast, striatal cerebral blood flow was not altered by temperature modulation during reperfusion. These results suggest that inhibition of ROS production accompanied with suppression of xanthine formation is implicated in the neuroprotection of postischemic hypothermia.

Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats

Horiguchi Takashi, Kis Bela, Rajapakse Nishadi, Shimizu Katsuyoshi, Busija David W.

Stroke 34 （ 4 ） 1015 - 1020 2003年04月

ISSN 0039-2499

Background and Purpose - The role of mitochondrial ATP-sensitive potassium channels (mitoK_ATP) in ischemic tolerance has been well documented in heart, but little work has been done in brain. To investigate the involvement of mitoK_ATP activation in chemical preconditioning in brain, we examined the effect of 5-hydroxydecanoate (5-HD), a selective mitoK_ATP blocker, on neurotoxin 3-nitropropionic acid (3-NPA)-induced ischemic tolerance to transient focal cerebral ischemia in rats. Methods - Male Wistar rats were administrated 3-NPA (20 mg/kg IP; n = 16) or vehicle (saline; n = 16) 3 days before temporary occlusion (120 minutes) of the middle cerebral artery; 5-HD (40 mg/kg IP; n = 16) was injected 20 minutes before 3-NPA administration. Infarct volumes were measured 4 days after reperfusion. To directly investigate whether chemical preconditioning activates mitoK_ATP, we tested the effect of prior incubation with 1 mmol/L 5-HD on 300 μmol/L 3-NPA-induced alterations of mitochondrial membrane potential (ΔΨ_m) in cultured neurons and astrocytes using the fluorescent dye tetramethylrhodamine ethyl ester. Results - Treatment with 3-NPA exhibited a 16% reduction (P<0.05) and 23% reduction in infarct volume (P<0.01) for total brain and cortex, respectively. Pretreatment with 5-HD completely abolished the neuroprotective effect of chemical preconditioning. In cultured cells, 3-NPA resulted in mitochondrial depolarization. This change of ΔΨ_m was completely blocked by 5-HD pretreatment. Conclusions - These results strongly suggest that opening of mitoK_ATP plays a key role as the trigger in the development of 3-NPA-induced ischemic tolerance in brain.

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Protective effect of a new nonpeptidyl mimetic of SOD, M40401, against focal cerebral ischemia in the rat

Shimizu Katsuyoshi, Rajapakse Nishadi, Horiguchi Takashi, Payne R. Mark, Busija David W.

Brain Research 963 （ 1-2 ） 8 - 14 2003年02月

ISSN 0006-8993

We tested the neuroprotective effects of M40401, a new, low molecular weight (511.4 Da) maganese superoxide dismutase mimetic, against 90 min of middle cerebral artery occlusion (MCAO) in male Wistar rats. Animals received a single injection of vehicle (n=8), 1 mg/kg (n=6), or 3 mg/kg (n=7) 30 min before MCAO. Total lesion volume was reduced only in the group receiving 3 mg/kg M40401 (163.5±18.7 versus 43.4±7.0 mm³, for vehicle and M40401, respectively; P<0.05), with almost complete reduction of lesion volume in the cortex but little protection in the basal ganglia. Neurological score was also improved in this group. The dose of 1 mg/kg M40401 had smaller and inconsistent effects on lesion parameters. Administration of a single dose of 3 mg/kg M40401 at 60 min of MCAO or at the end of MCAO (90 min) failed to significantly reduce lesion volume. A single dose of M40401 plus prolonged infusion into the post-MCAO period also failed to decrease lesion volume significantly. These data indicate that M40401 protects cerebral tissue from ischemic insult when administered before MCAO, probably by limiting damage mediated by detrimental actions of superoxide anion. © Elsevier Science B.V. All rights reserved.

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Nitric Oxide (NO) is involved in development of cortical spreading depression (CSD)-induced ischemic tolerance to transient focal cerebral ischemia in rats

Takashi Horiguchi, K Shimizu, DW Busija

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 23(Sup-1) S472 2003年

研究論文（国際会議プロシーディングス）, 共著

Diazoxide induces delayed preconditioning in cultured rat cortical neurons

Kis, B. Rajapakse, N. C. Snipes, J. A. Nagy, K. Horiguchi, T.; Busija, D. W.

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 23(Sup-1) S480 2003年

研究論文（国際会議プロシーディングス）, 共著

Neuroprotection role of adenosine under hypothermia in the rat global ischemia involves inhibition of not dopamine release but delayed postischemic hypoperfusion

Horiguchi Takashi, Shimizu Katsuyoshi, Ogino Masahiro, Yamaguchi Noriyuki, Suga Sadao, Inamasu Joji, Kawase Takeshi

Brain Research 952 （ 2 ） 222 - 231 2002年10月

ISSN 0006-8993

Adenosine (ADO) has an important role in the ischemic brain as an endogenous neuroprotective factor. On the other hand, intraischemic hypothermia ameliorates ischemic neuronal injury. To investigate the effect of ADO during intraischemic mild hypothermia, the extracellular concentration of ADO, its metabolites, dopamine (DA), and local cerebral blood flow were measured in rat striatum during and after 20 min of global ischemia. Additionally, the histopathological outcome was estimated after 48 h of recirculation. Three experimental groups were used: (1) a normothermic group (NT) maintained at 37°C during and after ischemia; (2) a hypothermic group (HT), exposed to intraischemic hypothermia (32.0°C) and postischemic normothermia; and (3) a hypothermia plus theophylline group (HT+T), with the same temperature conditions as in the HT group, combined with intravenously administration of theophylline (10 mg/kg), an antagonist of adenosine receptor, which was given 10 min before ischemia. The level of ADO in HT was significantly higher than ADO levels in NT. In contrast, ischemic DA release was significantly inhibited in HT compared with NT. Theophylline administration had no effect on intraischemic hypothermia induced modulation of extracellular ADO and DA concentration. The postischemic delayed hypoperfusion was ameliorated in HT, and theophylline eliminated this effect in HT+T. A protective effect on histopathological outcome was observed in HT and HT+T. These results suggest that ADO plays an essential role in the inhibition of postischemic delayed hypoperfusion, but this effect is not crucial role in the protective effect induced by intraischemic hypothermia. © 2002 Elsevier Science B.V. All rights reserved.

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Transient forebrain ischemia induces expression of serine/threonine protein phosphatase 1 mRNA in the vulnerable regions of gerbil brain

Horiguchi Takashi, Shima Hiroshi, Suga Sadao, Ogino Masahiro, Shimizu Katsuyoshi, Toya Shigeo, Nagao Minako, Kawase Takeshi

Neuroscience Letters 325 （ 2 ） 115 - 118 2002年06月

ISSN 0304-3940

Apoptosis is thought to be implicated in delayed neuronal cell death following transient forebrain ischemia. Recently, apoptosis in neurons induced by an inhibitor of serine/threonine (ser/thr) protein phosphatases (PPs) has been reported. In this study, we investigated the effect of transient forebrain ischemia on the expression of ser/thr PPs in the brain of Mongolian gerbils. At 24 h after 5-min bilateral carotid artery occlusion, Northern blotting analysis revealed the increase of PP1 mRNA expression in the vulnerable CA1 region of the hippocampus and striatum, but not in the cortex and CA3 region. In contrast, the protein level of PP1 detected by Western blotting analysis decreased in all regions. We conclude that the inhibition in PPs expression in the vulnerable regions may affect cell death after transient forebrain ischemia. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

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Mild hypothermia for hemispheric cerebral infarction after evacuation of an acute subdural hematoma in an infant

Inamasu Joji, Ichikizaki Kiyoshi, Matsumoto Shinji, Nakamura Yoshiki, Saito Ryoichi, Horiguchi Takashi, Kanai Ryuichi

Child's Nervous System 18 （ 3-4 ） 175 - 178 2002年04月

ISSN 0256-7040

The use of mild hypothermia to treat hemispheric infarction after evacuation of an acute subdural hematoma in an infant is reported. The patient, a 2-year-old boy, presented with a deteriorating level of consciousness after a fall from a tree. Computed tomography (CT) scan revealed an acute subdural hematoma on the right side with marked midline shift, and emergency evacuation of the hematoma was performed. The postoperative course was uneventful until the patient's intracranial pressure (ICP) rose and his condition deteriorated 3 days after surgery. CT scan revealed a hemispheric infarction on the injured side. Mild hypothermia was induced to control the ICP and protect the brain. While the hypothermia was effective in lowering the elevated ICP, it failed to arrest progression of the infarction. The patient was discharged with mild disability 2 months after the injury. No serious complications occurred during or after the hypothermia. Our experience indicates that hypothermia can be a useful procedure for controlling the ICP in children with severe traumatic brain injury including acute subdural hematoma, although its capability to protect the brain from severe, progressive ischemia appears to be limited.

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救命救急センターにおける近赤外線分光分析装置(NIRO-300)を用いた脳酸素代謝障害の評価

堀口崇, 斎藤良一, 稲桝丈司, 山本紳一郎, 菊野隆明, 中村芳樹, 市来嵜潔

日本救急医学会雑誌（(一社)日本救急医学会） 13 （ 4 ） 174 - 182 2002年04月

ISSN 0915-924X

意識レベルがJapan Coma Scaleで3桁であった14例(男9例,女5例,平均47.4歳)を対象に,近赤外線分光分析装置で測定した総ヘモグロビン濃度に対する酸素化ヘモグロビン濃度の割合を,上腕部測定での値(TA)と前額部測定での値(TB)で比較した.その結果,大脳半球に障害が及んでいない3例のみ,TBがTAより高値であった.大脳半球に障害が及んだ11例中,2例を除いてTBが減少し,TAよりも低値であった.この2例では出血に伴う血管外のヘモグロビンの影響が考えられた.各種ヘモグロビン濃度変化或いは他の検査所見と比較したところ,虚血脳における酸素代謝障害を鋭敏に捉えていることが示された.又,TBが内頸静脈酸素飽和度とよく相関しながら変化する症例も認めた

救命救急センターにおける近赤外線分光分析装置（NIRO-300）を用いた脳酸素代謝障害の評価ー第二報ー

堀口　崇、斉藤良一、稲桝丈司、山本紳一郎、菊野隆明、中村芳樹、市来嵜　潔

日本救急医学会雑誌 13 174 - 182 2002年

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Prolonged unilateral vasodilatation and brain edema in fulminant hepatic failure, associated with symptomatic seizure

Inamasu Joji, Nakamura Yoshiki, Yamamoto Shinichiro, Sakamoto Namiko, Saito Ryoichi, Horiguchi Takashi, Ichikizaki Kiyoshi

Clinical Neurology and Neurosurgery 104 （ 2 ） 157 - 160 2002年

ISSN 0303-8467

We report prolonged unilateral vasodilatation and hemispheric brain edema in a 49-year-old man with fulminant hepatic failure (FHF). The patient presented with a tonic-clonic seizure caused by a hypertensive subcortical hemorrhage in the left parietal lobe. Serial computed tomography (CT) scans showed progressive darkening of the ipsilateral hemisphere, suggesting hemispheric cerebral infarction, but the patient did not show clinical signs of deterioration. Brain magnetic resonance angiography showed dilation of the large arteries of the left hemisphere. Evaluation of cerebral blood flow 7 days postictus with single photon emission CT revealed marked ipsilateral hyperperfusion. The darkening of the hemisphere was brain edema elicited by hyperperfusion. Brain edema was reversible, disappearing 14 days postictus. Hemispheric brain edema was caused by unilateral cerebral vasodilatation and resultant hyperperfusion. Although brain edema is a major complication in FHF patients and cerebral hyperperfusion is responsible for edema formation, CT findings of these patients almost invariably show a bilateral lesion. Unilateral vasodilatation and subsequent hemispheric hyperperfusion may be due to overproduction of vasodilators, already abundant in the brains of patients with severe hepatic failure, by seizure activity. Copyright © 2002 Elsevier Science B.V.

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MitoK_ATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat

Shimizu Katsuyoshi, Lacza Zsombor, Rajapakse Nishadi, Horiguchi Takashi, Snipes James, Busija David W.

American Journal of Physiology - Heart and Circulatory Physiology 283 （ 3 52-3 ） 2002年

ISSN 0363-6135

We investigated effects of diazoxide, a selective opener of mitochondrial ATP-sensitive K⁺ (mitoK_ATP) channels, against brain damage after middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (0.4 or 2 mM in 30 μl saline) or saline (sham) was infused into the right lateral ventricle 15 min before MCAO. Neurological score was improved 24 h later in the animals treated with 2 mM diazoxide (13.8 ± 0.7, n = 13) compared with sham treatment (9.5 ± 0.2, n = 6, P < 0.01). The total percent infarct volume (MCAO vs. contralateral side) of sham treatment animals was 43.6 ± 3.6% (n = 12). Treatment with 2 mM diazoxide reduced the infarct volume to 20.9 ± 4.8% (n = 13, P < 0.05). Effects of diazoxide were prominent in the cerebral cortex. The protective effect of diazoxide was completely prevented by the pretreatment with 5-hydroxydecanoate (100 mM in 10 μl saline), a selective blocker of mitoK_ATP channels (n = 6). These results indicate that selective opening of the mitoK_ATP channel has neuroprotective effects against ischemia-reperfusion injury in the rat brain.

MitoK<inf>ATP</inf> opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat

Shimizu K., Lacza Z., Rajapakse N., Horiguchi T., Snipes J., Busija D.W.

American Journal of Physiology - Heart and Circulatory Physiology 283 （ 3 52-3 ） 2002年

ISSN 03636135

We investigated effects of diazoxide, a selective opener of mitochondrial ATP-sensitive K+ (mitoKATP) channels, against brain damage after middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (0.4 or 2 mM in 30 μl saline) or saline (sham) was infused into the right lateral ventricle 15 min before MCAO. Neurological score was improved 24 h later in the animals treated with 2 mM diazoxide (13.8 ± 0.7, n = 13) compared with sham treatment (9.5 ± 0.2, n = 6, P < 0.01). The total percent infarct volume (MCAO vs. contralateral side) of sham treatment animals was 43.6 ± 3.6% (n = 12). Treatment with 2 mM diazoxide reduced the infarct volume to 20.9 ± 4.8% (n = 13, P < 0.05). Effects of diazoxide were prominent in the cerebral cortex. The protective effect of diazoxide was completely prevented by the pretreatment with 5-hydroxydecanoate (100 mM in 10 μl saline), a selective blocker of mitoKATP channels (n = 6). These results indicate that selective opening of the mitoKATP channel has neuroprotective effects against ischemia-reperfusion injury in the rat brain.

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