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

Horikawa, Naotsugu; Kuribayashi, Yoshikazu; Itoh, Natsuko; Nishioka, Mizue; Matsui, Kazuki; Kawamura, Nobuko; Ohashi, Naohito

doi:10.1254/jjp.85.271

Cited by 21 publications

(21 citation statements)

References 23 publications

(31 reference statements)

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“…Therefore, it is supposed that the protective effect of sabiporide on BBB dysfunction may be, at least partially, involved in its neuroprotective effect against ischemic injury, although we cannot clarify how much of this BBB protection will contribute to the sabiporide's effect on brain damage. Consistent with our results, SM-20220 which is known to protect neurons against excitotoxicity in rat cortex (Matsumoto et al, 2004) has shown a significant suppressing effect on Evans blue extravasation during cerebral ischemia (Horikawa et al, 2001). In addition, cariporide, a well known NHE-1 inhibitor preserving neuroprotective effects (Luo et al, 2005), also reduced S-100B release in serum during cardiac surgery, suggesting its protective effect on BBB permeability (Scholz et al, 2003).…”

Section: Discussionsupporting

confidence: 90%

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The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

2010

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Section: Discussionsupporting

confidence: 90%

“…It has been suggested that the protective effects of NHE-1 inhibitor on ischemic brain injury may be mediated, at least in part, by the prevention of endothelial dysfunction (Horikawa et al, 2001). Our results support this concept by showing the protective effect of sabiporide against BBB hyperpermeability in a rat brain ischemia model.…”

Section: Discussionmentioning

confidence: 99%

The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

2010

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Section: Discussionmentioning

confidence: 99%

“…An amelioration of endothelial cell dysfunction after transient ischemia has been observed with NHE inhibition (37). NHE inhibition was also associated with reduced blood-brain barrier disruption, improved postischemic perfusion, and neuroprotection (37). In astrocyte cultures, oxygen and glucose deprivation resulted in a large increase in intracellular sodium and an increase in cell volume (10).…”

Section: Discussionmentioning

confidence: 99%

N-Methyl-isobutyl-amiloride Ameliorates Brain Injury When Commenced Before Hypoxia Ischemia in Neonatal Mice

et al. 2006

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Under physiologic conditions, brain intracellular pH (pH i ) is maintained at 7.03. Rebound brain intracellular alkalosis has been observed in experimental models and adult stroke after hypoxia/ ischemia (HI). In term infants with neonatal encephalopathy (NE), an association exists between the magnitude of brain alkalosis and neurodevelopmental outcome, and there is increasing evidence to suggest that alkalosis may be deleterious to cell survival. Activation of the Na ϩ /H ϩ exchanger (NHE) is thought to be responsible for the rapid normalization of pH i and rebound alkalosis after reperfusion. We hypothesized that N-methyl-isobutyl-amiloride (MIA), an inhibitor of the NHE, would reduce brain injury in a model of neonatal HI. Seven-day-old mice underwent left carotid artery occlusion followed by exposure to 8% oxygen for 30 min (moderate insult) or 1 h (severe insult). Animals received MIA or saline 8 hourly starting 30 min before HI. Outcome was determined at 48 h by measuring viable tissue in the injured hemisphere (severe insult) or injury score and TUNEL staining (moderate insult). After the severe insult, MIA had a significant neuroprotective effect increasing forebrain tissue survival from 44% to 67%. After the moderate insult, damage was localized to the hippocampus where treatment resulted in a significant reduction in injury score and in TUNEL-positive cells. MIA was also shown to have a significant overall neuroprotective effect based on injury score after the moderate insult. Amiloride analogues are neuroprotective when commenced before HI in a mouse model. P erinatal HI affects approximately one to two per 1000 term infants per year in the United Kingdom and leads to death or severe impairment in more than 750 infants annually (1) Over the past 20 y, studies using phosphorus ( 31 P) and ( 1 H) proton magnetic resonance spectroscopy (MRS) in both infants with NE (2-4) and experimental models (5,6) have characterized the biphasic disruption of cerebral energetics that occurs in the hours after HI. These observations have led to the concept of a "therapeutic window" after HI, during which intervention may ameliorate the severity of brain injury. Recent results from the first randomized trials of mild hypothermia in term infants with NE are promising (7-9); however, considerable work is still required to optimize cooling strategies in the newborn. Furthermore, there is a growing impression that optimum neuroprotection may involve the use of more than one therapy, targeting different parts of the neurotoxic cascade.Under physiologic conditions, brain pH i is maintained at approximately 7.03; the NHE tightly regulates both pH i and cell volume by extruding protons from and taking sodium up into cells (10). A remarkable observation from the studies employing 31 P MRS in infants with NE was that during the secondary phase of energy decline occurring from 8 to 24 h after birth, brain pH i was not acidic but alkaline (pH i 7.1-7.4) (11). Some evidence suggests that excessive activation of the NHE aft...

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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]. In the same model, another selective NHE blocker, sabiporide (3 mg/kg, i.v.…”

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

confidence: 95%

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

Cited by 21 publications

References 23 publications

The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

N-Methyl-isobutyl-amiloride Ameliorates Brain Injury When Commenced Before Hypoxia Ischemia in Neonatal Mice

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

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