Spinasterol alleviates nerve injury and neurological deficits after ischemic stroke via regulating Src

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Objectives Spinasterol (Spin) demonstrates therapeutic potential against ischemic stroke/reperfusion (IS/R)-induced nerve injury. This study aimed to investigate Spin’s neuroprotection in IS/R through Src-mediated microglial injury.Methods IS/R was modeled in SD rats via middle cerebral artery occlusion/reperfusion (MCAO/R). Effect of Spin (2 mg/kg) on MCAO/R rats was evaluated through the intraperitoneal injection. Src (2 × 108 U/mL, 5 μL) overexpression in MCAO/R rats was performed by the lentiviral vector intracerebroventricular (ICV) injection. Neurological deficits were assessed using Morris water maze (MWM) and hanging-wire tests. The oxidative stress (malondialdehyde (MDA), superoxide dismutase (SOD)), and inflammatory response (IL-6, IL-1β, TNF-α) were quantified via ELISA. Src, Nfkb, and p38 Mapk expression were analyzed by qRT-PCR. LPS-stimulated microglia cells to evaluate the effect of Spin and Src on microglial injury.Results Upregulated Src expression was observed in brain tissues after MCAO/R and LPS-induced BV-2 cells. Spin improved cognitive and motor functions in MCAO/R rats. Spin mitigated water content, oxidative stress (decreased MDA, increased SOD), suppressed the IL-6, IL-1β, and TNF-α levels in MCAO/R rats. In LPS-induced BV-2 injury model, Spin reduced the inflammation, oxidative stress and suppressed the M1 marker (iNOs), while enhancing the M2 marker (Arg-1). Src overexpression abolished anti-inflammatory and antioxidant effects of Spin both in vivo and in vitro models.Discussion Spin showed a protective effect on nerve injury and neurological deficits caused by MCAO/R. The possible mechanism of Spin in IS/R might be that Spin could relieve the inflammation, oxidative stress, and M1 polarization of microglial cells by regulating Src.

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