Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury.

Neuroinflammation plays an important role in the pathophysiology of surgical brain injury (SBI). Phosphoinositide 3-kinase gamma (PI3K_γ), predominately expressed in immune and endothelial cells, activates multiple inflammatory responses. In the present study, we investigated the role of PI3K_γ and PI3K_γ-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_γ pharmacological inhibitor (AS252424 or AS605240) was administered intraperitoneally. PI3K_γ siRNA, human recombinant active-PI3K_γ 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_γ 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_γ inhibitors AS252424 and AS605240 reduced brain water content surrounding corticotomy and improved neurological function after SBI. SBI increased and PI3K_γ 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_γ protein and active-PDE3B protein countered the protective effect of AS252424. PI3K_γ siRNA reduced PI3K_γ levels, decreased brain water content within peri-resection brain tissues, and improved neurological function after SBI. Collectively, our findings suggest that PI3K_γ contributed to neuroinflammation after SBI. The use of selective PI3K_γ inhibitors may be a novel approach to ameliorating SBI via their anti-inflammation effects. [ABSTRACT FROM AUTHOR]