Cerebroprotective properties of SM-20220, a potent Na+/H+ exchange inhibitor, in transient cerebral ischemia in rats

Kuribayashi, Yoshikazu; Itoh, Natsuko; Kitano, Masahumi; Ohashi, Naohito

doi:10.1016/s0014-2999(99)00645-7

Cited by 46 publications

(32 citation statements)

References 23 publications

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“…immediately after initiation of ischemia) reduced total infarction area by ~50%, and partially prevented formation of brain edema [96]. These effects may be relevant to preservation of blood-brain barrier function and improved reperfusion rates [97], as well as to reduced accumulation of leukocytes in damaged brain tissue [98].…”

Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 94%

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Mongin

2007

Pathophysiology

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The mechanisms of brain tissue damage in stroke are strongly linked to the phenomenon of excitotoxicity, which is defined as damage or death of neural cells due to excessive activation of receptors for the excitatory neurotransmitters glutamate and aspartate. Under physiological conditions, ionotropic glutamate receptors mediate the processes of excitatory neurotransmission and synaptic plasticity. In ischemia, sustained pathological release of glutamate from neurons and glial cells causes prolonged activation of these receptors, resulting in massive depolarization and cytoplasmic Ca 2+ overload. The NMDA subtype of glutamate receptors is particularly important as it represents the main initial route for the Ca 2+ influx. High cytoplasmic levels of Ca 2+ activate many degradative processes that, depending on the metabolic status, cause immediate or delayed death of neural cells. This traditional view has been expanded by a number of observations that implicate Cl − channels and several types of non-channel transporter proteins, such as the Na + ,K + ,2Cl − cotransporter, Na + /H + exchanger, and Na + /Ca 2+ exchanger, in the development of glutamate toxicity. Some of these ion transporters increase tissue damage by promoting pathological cell swelling and necrotic cell death, while others contribute to a long term accumulation of cytoplasmic Ca 2+ . This brief review is aimed at illustrating how the dysregulation of various ion transport processes combine in a 'perfect storm' that disrupts neural ionic homeostasis and culminates in the irreversible damage and death of neural cells. The clinical relevance of individual transporters as targets for therapeutic intervention in stroke is also briefly discussed.

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Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 94%

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Mongin

2007

Pathophysiology

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“…Inhibition of NHE activity with nonselective inhibitor EIPA (amiloride derivative ethylisopropylamiloride) or a potent NHE inhibitor SM-20220 (N-aminoiminomethyl-1-methyl-1-indole-2-carboxamide methanesulfonate) significantly reduces loss of gerbil CA1 pyramidal neurons after global ischemia (Phillis et al, 1999) and the increase in rat brain Na ϩ and water content after focal ischemia (Kuribayashi et al, 1999).…”

Section: Namentioning

confidence: 99%

“…These noncorrelated effects between cell death and edema were also found with the NHE inhibitor SM20220. It was shown that although SM20220 (0.3 mg/kg) significantly reduced brain edema at 4 h reperfusion after 2 h MCAO in rats, it failed to reduce the infarction (Kuribayashi et al, 1999). However, continuous administration of SM20220 during reperfusion concurrently improved ischemic infarct formation, brain edema, and neutrophil accumulation (Suzuki et al, 2002).…”

Section: Inhibition Of Nhe1 Activity Fails To Reduce Ischemic Edema Fmentioning

confidence: 99%

Decreased Neuronal Death in Na⁺/H⁺Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia

Luo¹,

Chen²,

Kintner³

et al. 2005

J. Neurosci.

110

178

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Na ϩ /Hϩ exchanger isoform 1 (NHE1) is a major acid extrusion mechanism after intracellular acidosis. We hypothesized that stimulation of NHE1 after cerebral ischemia contributes to the disruption of Na ϩ homeostasis and neuronal death. In the present study, expression of NHE1 was detected in cultured mouse cortical neurons. Three hours of oxygen and glucose deprivation (OGD) followed by 21 h of reoxygenation ( ϩ/ϩ mice. NHE1 ϩ/ϩ mice treated with HOE 642 or NHE1 heterozygous mice exhibited a ϳ33% decrease in infarct size ( p Ͻ 0.05). These results imply that NHE1 activity disrupts Na ϩ and Ca 2ϩ homeostasis and contributes to ischemic neuronal damage.

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“…Recently, we indicated that activation of the NHE plays a key role in the aggravation of ischemic injury in the brain as well as in the heart and that the NHE inhibitor SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate, Fig. 1) prevents ischemic brain damage such as that caused by infarction (5,6) and reduces the increase in Na + content and the formation of edema (5). SM-20220 reduced the extent of hypoxia-reoxygenation injury in cultured neurons and glia (7).…”

Section: /Hmentioning

confidence: 99%

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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Cerebroprotective properties of SM-20220, a potent Na+/H+ exchange inhibitor, in transient cerebral ischemia in rats

Cited by 46 publications

References 23 publications

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Decreased Neuronal Death in Na⁺/H⁺Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia

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

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Cerebroprotective properties of SM-20220, a potent Na+/H+ exchange inhibitor, in transient cerebral ischemia in rats

Cited by 46 publications

References 23 publications

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Decreased Neuronal Death in Na+/H+Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia

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

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Decreased Neuronal Death in Na⁺/H⁺Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia