Blockade of the SP/NK1 receptor axis: multimodal neuroprotection via inflammatory suppression, hypoxic modulation, and lympho-vascular remodeling in global cerebral ischemia.

Transient global cerebral ischemia (tGCI), often precipitated by cardiac arrest, triggers severe neuroinflammation, oxidative stress, and hypoxia, culminating in diffuse delayed neuronal death and debilitating cognitive-affective dysfunctions. Substance P (SP) and its neurokinin-1 (NK1) receptor act as critical upstream mediators in this pathological cascade. To interrogate this biological pathway and rescue acute stroke-induced behavioral deficits, this study investigated the multifaceted neuroprotective efficacy of the NK1 receptor antagonist maropitant, utilizing a rat two-vessel occlusion (2VO) model as a translational platform. Male Wistar rats were divided into Sham (CON), Ischemia-Reperfusion (I/R), and I/R + Maropitant (I/R + MAR; 10 mg/kg, i.p., immediately post-ischemia) groups. Following a 60-minute occlusion and 24-hour reperfusion, behavioral paradigms (Open Field, Elevated Plus Maze, Forced Swim, Novel Object Recognition) were conducted. Subsequent biochemical (TNF-α, MPO, Caspase-3, HIF-1α, VEGF, BDNF) and histopathological/immunohistochemical (H&E, CD34, LCA, D2-40) analyses were performed on serum and hippocampal/cortical tissues. Maropitant administration significantly ameliorated I/R-induced memory impairment and mitigated anxiety- and depressive-like behaviors without altering general locomotion. Biochemically, targeted NK1 receptor blockade markedly attenuated central and systemic levels of TNF-α, MPO, Caspase-3, HIF-1α, and VEGF, while modulating stress-induced BDNF surges. Histopathologically, maropitant preserved cytoarchitecture by significantly reducing necrotic and degenerative cell counts across the cerebral cortex, CA3, and dentate gyrus. Crucially, immunohistochemical evaluation revealed that while maropitant suppressed post-ischemic leukocyte infiltration (LCA), it distinctly promoted functional neovascularization (CD34) and robust lymphatic vessel expansion (D2-40), facilitating tissue clearance. Targeted pharmacological blockade of the SP/NK1 receptor axis provides robust neuroprotection by dampening neuroinflammatory and apoptotic cascades while driving constructive lympho-vascular remodeling. These findings highlight NK1 receptor antagonism as a highly promising therapeutic strategy for mitigating acute ischemic brain injury and associated functional deficits.