SM-20220, a Potent Na+/H+ Exchange Inhibitor, Improves Consciousness Recovery and Neurological Outcome Following Transient Cerebral Ischaemia in Gerbils

Kuribayashi, Yoshikazu; Itoh, Natsuko; Horikawa, Naotsugu; Ohashi, Naohito

doi:10.1211/0022357001774057

Cited by 35 publications

(16 citation statements)

References 20 publications

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“…SM-20220 reduced the extent of hypoxia-reoxygenation injury in cultured neurons and glia (7). Furthermore, SM-20220 improves neurological outcome and survival rate (8) and may be a potential therapy for the treatment of acute stroke. Brain tissue consumes extremely high levels of oxygen and glucose, and maintenance of the cerebral blood flow is a prerequisite *Corresponding author.…”

Section: /Hmentioning

confidence: 98%

Na+/H+ Exchange Inhibitor SM-20220 Improves Endothelial Dysfunction Induced by Ischemia-Reperfusion

Horikawa

Kuribayashi

Itoh

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Endothelial cells play an important role in the physiologic homeostasis of the cerebral circulation. Previously, we showed that the Na + / H + exchanger (NHE) inhibitor SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate) improved ischemic brain injury. In this study, we investigated the effect of SM-20220 on cerebrovascular dysfunction after ischemia-reperfusion, focusing on the kinds of dysfunction that involved endothelial function. In cultured bovine brain microvascular endothelial cells (BBMCs), the IC 50 value for the NHE activity of SM-20220 was 4´10-8 M. SM-20220 also reduced the cell injury induced by hypoxia/ aglycemia-reoxygenation in BBMCs, with statistical significance at 10 -7 M (P<0.05). Next, the effect of SM-20220 on disruption of the blood-brain barrier and cerebral blood flow were evaluated using transient middle cerebral artery (MCA) occlusion models. Intravenous infusion of SM-20220 (0.4 mg/ kg per hour for 1 h) attenuated the extravasation of Evans blue, a blood-brain barrier disruption indicator, into cerebral tissue on the day after transient ischemia (P<0.05). The occlusion of the MCA decreased the cerebral blood flow in the MCA territory by about 20%, and only about 45% of the preischemic value was recovered at 1-h reperfusion. A bolus injection of SM-20220 (1 mg/kg, i.v.) improved the postischemic hypoperfusion by about 75%, without causing changes in the systemic blood pressure. These results indicate that the protective effect of NHE inhibitor on ischemic brain injury may be at least partially mediated by the prevention of endothelial dysfunction.

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Section: /Hmentioning

confidence: 98%

Na+/H+ Exchange Inhibitor SM-20220 Improves Endothelial Dysfunction Induced by Ischemia-Reperfusion

Horikawa

Kuribayashi

Itoh

et al. 2001

Japanese Journal of Pharmacology

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“…2,10,18,19) Our previous study showed that SM-20220 prevented the infarction in a rat transient MCA occlusion model 10,11) ; however, the relationship between the timing of drug administration and its beneficial effects was not clear. In the present study, we investigated the dependence of the effect of SM-20220 on infarct size on the dose and on the timing of drug administration.…”

Section: Discussionmentioning

confidence: 99%

“…10) Furthermore, SM-20220 improved the neurological outcome and survival rate in gerbil stroke models. 11) These results suggest that the NHE inhibitor may represent a new class of drugs for the treatment of ischemic brain injury. In this study, we used a rat transient stroke model to investigate the relationship between the neuroprotective effect of SM-20220 and the timing of its administration.…”

mentioning

confidence: 93%

Relationship between the Neuroprotective Effect of Na<SUP>+</SUP>/H<SUP>+</SUP> Exchanger Inhibitor SM-20220 and the Timing of Its Administration in a Transient Middle Cerebral Artery Occlusion Model of Rats

Horikawa¹,

Kuribayashi²,

Matsui³

et al. 2001

Biological & Pharmaceutical Bulletin

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The aim of this study was to determine the relationship between the neuroprotective effect of SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate) and the timing of its administration in an experimental stroke model. Two hours of occlusion followed by 22 h of perfusion of the left middle cerebral artery (MCA) was performed by inserting a nylon thread into the MCA to occlude it, and pulling the thread to initiate reperfusion. Intravenous infusion of SM-20220 for 1 h reduced the infarct volume at doses of 0.2-0.8 mg/kg in a dose-dependent manner without causing changes in the systemic arterial blood pressure or blood gases, when SM-20220 administration was started 1 h after the onset of occlusion. Administration of SM-20220 at a dose of 0.4 mg/kg also reduced the edema formation induced by ischemia. In contrast, SM-20220 failed to reduce the infarction, even at 1.6 mg/kg, when administration was started 2 h after the onset of occlusion. Thus, the therapeutic time window of SM-20220 for this transient MCA occlusion model is 1 h. Daily administration of SM-20220 (0.4 mg/kg) for the 7 d following 1.5 h of middle cerebral artery occlusion reduced the infarct volume with statistical significance ( pϽ0.05), showing that SM-20220 did not merely delay but prevented ischemic damage. Key words Naϩ /H ϩ exchanger; brain ischemia; infarction; SM-20220; edema; therapeutic time window centage of the area of the left hemisphere for each coronal section. The infarct volume was calculated by integration of the infarct areas and the areas of the left hemisphere that were determined for the five coronal sections. Measurement of Arterial Blood Pressure, Gases, and pH In some animals, a femoral artery was cannulated to directly and continuously measure the systemic arterial blood pressure with a pressure transducer (P10EZ, Nihon Kohden, Osaka, Japan) attached to a blood-pressure amplifier (AP-641G, Nihon Kohden) and to sample blood for the analysis of blood gases and pH using I-STAT (Fuso Chemicals, Osaka, Japan). Measurement of Cerebral Water ContentTo measure the brain water content, rats were decapitated 4 h after the onset of reperfusion and the left hemisphere of the occluded MCA territory was cut into 4-mm-thick slices (1 mm anterior-3 mm posterior to the bregma).10) The water content was determined by the dry-weight method. 13)Experimental Protocol The experimental protocol is shown in Fig. 1. SM-20220 was dissolved in 8% polyethylene glycol 400 (w/v) to 0.4 mg/ml and diluted with the same solution to 0.04, 0.08, 0.16, and 0.32 mg/ml. The diluted SM-20220 or just the solution as vehicle was given as an intravenous infusion (5 ml/kg/h) for 1 h using an infusion pump (model 100, KD Scientific, U.S.A.).For the first experiment, the administration of SM-20220 or vehicle was started 1 h after the onset of occlusion, and physiological variables were measured before surgery, before drug administration, and 30 min after the onset of reperfusion; the infarct size was measured 22 h after the onset.For the sec...

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“…Yorkshire-Duroc pigs treated with cariporide (HOE 642), a potent and selective inhibitor of NHE-1, at the onset of a 90 min deep hypothermic circulatory arrest demonstrated improved neurologic recovery (Castellá et al, 2005). Similarly, inhibition of NHE-1 with N-[aminoiminomethyl]-1-methyl-1H-indole-2-carboxamide methanesulfonate (SM-20220) improved neurologic function in a gerbil model of transient global cerebral ischemia (Kuribayashi et al, 2000). Administration of the NHE-1 inhibitor ethylisopropylamiloride (EIPA) prior to bilateral carotid artery occlusion in gerbils resulted in decreased hippocampal neuronal cell death and improved neurologic function (Phillis et al, 1999).…”

Section: Global Ischemiamentioning

confidence: 99%

“…The IC 50 for the human NHE-1 are as follows: Amiloride = 10.7 µM, Cariporide = 0.08 µM, T-165229 = 13 nM. Importantly, the NHE inhibitors HOE 642 and SM-20220 not only reduce cell death and edema, but also improve neurological function in in vivo ischemia models, and have demonstrated benefits when administered after ischemia (Kintner et al, 2007b;Kuribayashi et al, 2000).…”

Section: Pharmacological Approachmentioning

confidence: 99%

The Na+/H+ Exchanger-1 as a New Molecular Target in Stroke Interventions

Chanana¹,

Sun²,

Ferrazzano³

2012

Advances in the Preclinical Study of Ischemic Stroke

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SM-20220, a Potent Na+/H+ Exchange Inhibitor, Improves Consciousness Recovery and Neurological Outcome Following Transient Cerebral Ischaemia in Gerbils

Cited by 35 publications

References 20 publications

Na+/H+ Exchange Inhibitor SM-20220 Improves Endothelial Dysfunction Induced by Ischemia-Reperfusion

Na+/H+ Exchange Inhibitor SM-20220 Improves Endothelial Dysfunction Induced by Ischemia-Reperfusion

Relationship between the Neuroprotective Effect of Na<SUP>+</SUP>/H<SUP>+</SUP> Exchanger Inhibitor SM-20220 and the Timing of Its Administration in a Transient Middle Cerebral Artery Occlusion Model of Rats

The Na+/H+ Exchanger-1 as a New Molecular Target in Stroke Interventions

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