Lysophosphatidic acid receptor 1 (LPA₁) plays critical roles in microglial activation and brain damage after transient focal cerebral ischemia.

BACKGROUND:Lysophosphatidic 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). METHODS:To 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. RESULTS:AM095 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. CONCLUSION:This 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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