Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury
Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury
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DOI：
10.1523/jneurosci.0546-15.2015
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发表时间：
2015-07-22
影响因子：
5.3
通讯作者：
Zhang, John H.
中科院分区：
文献类型：
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作者：
Huang, Lei;Sherchan, Prativa;Zhang, John H.
神经炎症在外科脑损伤（SBI）的病理生理学中起着重要作用。主要在免疫和内皮细胞中表达的磷酸肌醇3-激酶γ（PI 3 K γ）激活多种炎症反应。在本研究中，我们研究了PI 3 K γ和PI 3 K γ激活的磷酸二酯酶3B（PDE 3B）在SBI大鼠模型神经炎症中的作用。对152只雄性Sprague道利大鼠（体重280-350 g）进行SBI的部分右额叶皮质切除术模型。腹膜内给予PI 3 K γ药理学抑制剂（AS 252424或AS 605240）。脑室内施用PI 3 K γ siRNA、人重组活性-PI 3 K γ蛋白或人重组活性-PDE 3B蛋白。SBI后评估包括神经行为测试、脑含水量、Western印迹和免疫组织化学。SBI后切除周围脑组织中内源性PI 3 K γ水平升高，伴有脑含水量增加和神经功能缺损。SBI后内源性PDE 3B磷酸化有增加的趋势。选择性PI 3 K γ抑制剂AS 252424和AS 605240降低了皮质切除术周围的脑水含量，并改善了SBI后的神经功能。SBI增加和PI 3 K γ抑制剂降低切除周围脑组织中髓过氧化物酶、分化簇3、肥大细胞脱粒、E-选择素和IL-1的水平。直接给予人重组活性PI 3 K γ蛋白和活性PDE 3B蛋白抵消了AS 252424的保护作用。PI 3 K γ siRNA降低了PI 3 K γ水平，降低了切除术周围脑组织中的脑含水量，并改善了SBI后的神经功能。总的来说，我们的研究结果表明，PI 3 K γ有助于SBI后的神经炎症。使用选择性PI 3 K γ抑制剂可能是通过其抗炎作用改善SBI的新方法。
Neuroinflammation plays an important role in the pathophysiology of surgical brain injury (SBI). Phosphoinositide 3-kinase gamma (PI3K gamma), predominately expressed in immune and endothelial cells, activates multiple inflammatory responses. In the present study, we investigated the role of PI3K gamma and PI3K gamma-activated phosphodiesterase 3B (PDE3B) in neuroinflammation in a rat model of SBI. One hundred and fifty-two male Sprague Dawley rats (weight 280-350 g) were subjected to a partial right frontal lobe corticotomy model of SBI. A PI3K gamma pharmacological inhibitor (AS252424 or AS605240) was administered intraperitoneally. PI3K gamma siRNA, human recombinant active-PI3K gamma protein, or human recombinant active-PDE3B protein were administered intracerebroventricularly. Post-SBI assessments included neurobehavioral tests, brain water content, Western blot, and immunohistochemistry. Endogenous PI3K gamma levels were increased within peri-resection brain tissues after SBI, accompanied by increased brain water content and neurological functional deficits. There was a trend toward increased endogenous PDE3B phosphorylation after SBI. The selective PI3K gamma inhibitors AS252424 and AS605240 reduced brain water content surrounding corticotomy and improved neurological function after SBI. SBI increased and PI3K gamma inhibitor decreased levels of myeloperoxidase, cluster of differentiation 3, mast cell degranulation, E-selectin, and IL-1 in peri-resection brain tissues. Direct administration of human recombinant active-PI3K gamma protein and active-PDE3B protein countered the protective effect of AS252424. PI3K gamma siRNA reduced PI3K gamma levels, decreased brain water content within peri-resection brain tissues, and improved neurological function after SBI. Collectively, our findings suggest that PI3K gamma contributed to neuroinflammation after SBI. The use of selective PI3K gamma inhibitors may be a novel approach to ameliorating SBI via their anti-inflammation effects.