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Magnesium sulfate and nimesulide have synergistic effects on rescuing brain damage after transient focal ischemia.

ABSTRACT: Magnesium sulfate and nimesulide are commonly used drugs with reported neuroprotective effects. Their combination as stroke treatment has the potential benefits of decreasing individual drug dosage and fewer adverse effects. This study evaluated their synergistic effects and compared a low-dose combination with individual drug alone and placebo. Sprague-Dawley rats underwent 90?min of focal ischemia with intraluminal suture occlusion of the middle cerebral artery followed by reperfusion. The rats were randomly assigned to receive one of the following treatments: placebo, magnesium sulfate (MgSO?; 45?mg/kg) intravenously immediately after the induction of middle cerebral artery occlusion, nimesulide (6?mg/kg) intraperitoneally before reperfusion, and combined therapy. Three days after the ischemia-reperfusion insult, therapeutic outcome was assessed by 2,3,5-triphenyltetrazolium chloride staining and a 28-point neurological severity scoring system. Cyclooxygenase-2, prostaglandin E?, myeloperoxidase, and caspase-3 expression after treatment were evaluated using Western blot analyses and immunohistochemical staining, followed by immunoreactive cell analysis using tissue cytometry. Only the combination treatment group showed a significant decrease in infarction volume (10.93±6.54% versus 26.43±7.08%, p<0.01), and neurological severity score (p<0.05). Low-dose MgSO? or nimesulide showed no significant neuroprotection. There was also significant suppression of cyclooxygenase-2, prostaglandin E?, myeloperoxidase, and caspase-3 expression in the combination treatment group, suggesting that the combination of the two drugs improved the neuroprotective effects of each individual drug. MgSO? and nimesulide have synergistic effects on ischemia-reperfusion insults. Their combination helps decrease drug dosage and adverse effects. Combined treatment strategies may help to combat stroke-induced brain damage in the future.

SUBMITTER: Wang LC

PROVIDER: S-EPMC3335109 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Magnesium sulfate and nimesulide have synergistic effects on rescuing brain damage after transient focal ischemia.

Wang Liang-Chao LC Huang Chih-Yuan CY Wang Hao-Kuang HK Wu Ming-Hsiu MH Tsai Kuen-Jer KJ

Journal of neurotrauma 20120329 7

Magnesium sulfate and nimesulide are commonly used drugs with reported neuroprotective effects. Their combination as stroke treatment has the potential benefits of decreasing individual drug dosage and fewer adverse effects. This study evaluated their synergistic effects and compared a low-dose combination with individual drug alone and placebo. Sprague-Dawley rats underwent 90 min of focal ischemia with intraluminal suture occlusion of the middle cerebral artery followed by reperfusion. The rat ...[more]

PMID: 22332641

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Project description:BackgroundLysophosphatidic acid receptor 1 (LPA1) is in the spotlight because its synthetic antagonist has been under clinical trials for lung fibrosis and psoriasis. Targeting LPA1 might also be a therapeutic strategy for cerebral ischemia because LPA1 triggers microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed this possibility using a mouse model of transient middle cerebral artery occlusion (tMCAO).MethodsTo address the role of LPA1 in the ischemic brain damage, we used AM095, a selective LPA1 antagonist, as a pharmacological tool and lentivirus bearing a specific LPA1 shRNA as a genetic tool. Brain injury after tMCAO challenge was accessed by determining brain infarction and neurological deficit score. Role of LPA1 in tMCAO-induced microglial activation was ascertained by immunohistochemical analysis. Proinflammatory responses in the ischemic brain were determined by qRT-PCR and immunohistochemical analyses, which were validated in vitro using mouse primary microglia. Activation of MAPKs and PI3K/Akt was determined by Western blot analysis.ResultsAM095 administration immediately after reperfusion attenuated brain damage such as brain infarction and neurological deficit at 1 day after tMCAO, which was reaffirmed by LPA1 shRNA lentivirus. AM095 administration also attenuated brain infarction and neurological deficit at 3 days after tMCAO. LPA1 antagonism attenuated microglial activation; it reduced numbers and soma size of activated microglia, reversed their morphology into less toxic one, and reduced microglial proliferation. Additionally, LPA1 antagonism reduced mRNA expression levels of proinflammatory cytokines and suppressed NF-κB activation, demonstrating its regulatory role of proinflammatory responses in the ischemic brain. Particularly, these LPA1-driven proinflammatory responses appeared to occur in activated microglia because NF-κB activation occurred mainly in activated microglia in the ischemic brain. Regulatory role of LPA1 in proinflammatory responses of microglia was further supported by in vitro findings using lipopolysaccharide-stimulated cultured microglia, showing that suppressing LPA1 activity reduced mRNA expression levels of proinflammatory cytokines. In the ischemic brain, LPA1 influenced PI3K/Akt and MAPKs; suppressing LPA1 activity decreased MAPK activation and increased Akt phosphorylation.ConclusionThis study demonstrates that LPA1 is a new etiological factor for cerebral ischemia, strongly indicating that its modulation can be a potential strategy to reduce ischemic brain damage.

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Magnesium sulfate and nimesulide have synergistic effects on rescuing brain damage after transient focal ischemia.

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Magnesium sulfate and nimesulide have synergistic effects on rescuing brain damage after transient focal ischemia.

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