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Studies have reported that Prosaposin (PSAP) is neuroprotective in cerebrovascular diseases. We hypothesized that PSAP would reduce infarct volume by attenuating neuronal apoptosis and promoting cell survival through G protein-coupled receptor 37(GPR37)/PI3K/Akt/ASK1 pathway in middle cerebral artery occlusion (MCAO) rats. Two hundred and thirty-five male and eighteen female Sprague-Dawley rats were used. Recombinant human PSAP (rPSAP) was administered intranasally 1 h (h) after reperfusion. PSAP small interfering ribonucleic acid (siRNA), GPR37 siRNA, and PI3K specific inhibitor LY294002 were administered intracerebroventricularly 48 h before MCAO. Infarct volume, neurological score, immunofluorescence staining, Western blot, Fluoro-Jade C (FJC) and TUNEL staining were examined. The expression of endogenous PSAP and GPR37 were increased after MCAO. Intranasal administration of rPSAP reduced brain infarction, neuronal apoptosis, and improved both short- and long-term neurological function. Knockdown of endogenous PSAP aggravated neurological deficits. Treatment with exogenous rPSAP increased PI3K expression, Akt and ASK1 phosphorylation, and Bcl-2 expression; phosphorylated-JNK and Bax levels were reduced along with the number of FJC and TUNEL positive neurons. GPR37 siRNA and LY294002 abolished the anti-apoptotic effect of rPSAP at 24 h after MCAO. In conclusion, rPSAP attenuated neuronal apoptosis and improved neurological function through GPR37/PI3K/Akt/ASK1 pathway after MCAO in rats. Therefore, further exploration of PSAP as a potential treatment option in ischemic stroke is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Reperfusion exceeded time window may induce ischemia/reperfusion injury, increase hemorrhagic transformation, and deteriorate neurological outcomes in ischemic stroke models. However, the increasing clinical evidences supported that reperfusion even within 6-24 h may salvage ischemic tissue and improve neurological outcomes in selected large vessel occlusion patients, without inducing serious ischemia/reperfusion injury and hemorrhagic transformation. The underlying molecular mechanisms are less clear. In present study, we demonstrated that delayed recanalization at 3 days after permanent middle cerebral artery occlusion (MCAO) decreased infarct volumes and improved neurobehavioral deficits in rats, with no increasing animal mortality and intracerebral hemorrhage. Meanwhile, we observed that endogenous neuroprotective agent fibroblast growth factor 21 (FGF21) significantly increased in serum after MCAO, but which did not synchronously increase in penumbra due to permanent MCAO. Recanalization dramatically increased the endogenous FGF21 expression on neurons in penumbra after MCAO. We confirmed that FGF21 activated the FGFR1/PI3K/Caspase-3 signaling pathway, which attenuated neuronal apoptosis in penumbra. Conversely, knockdown of FGFR1 via FGFR1 siRNA abolished the anti-apoptotic effects of FGF21, and in part abrogated beneficial effects of recanalization on neurological outcomes. These findings suggested that delayed recanalization at 3 days after MCAO improved neurological outcomes in rats via increasing endogenous FGF21 expression and activating FGFR1/PI3K/Caspase-3 pathway to attenuate neuronal apoptosis in penumbra. Delayed recanalization at 3 days after ischemic stroke onset may be a promising treatment strategy in selected patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Autophagy activation exerts neuroprotective effects in the ischemic stroke model. Ezetimibe (Eze), a Niemann-Pick disease type C1-Like 1 (NPC1L1) pharmacological inhibitor, has been reported to protect hepatocytes from apoptosis via autophagy activation. In this study, we explored whether Eze could attenuate neuronal apoptosis in the rat model of middle cerebral artery occlusion (MCAO), specifically via activation of the AMPK/ULK1/autophagy pathway. Two hundred and one male Sprague-Dawley rats were subjected to transient MCAO followed by reperfusion. Eze was administered 1 h after MCAO. To elucidate the underlying molecular mechanism, Dorsomorphin, a selective AMPK inhibitor, and 3-methyladenine (3-MA), an autophagy inhibitor, were injected intracerebroventricularly before MCAO. Infarct volume, neurological score, brain cholesterol levels, immunofluorescence staining, Western blot, and Fluoro-Jade C (FJC) staining were used to evaluate the effects of Eze. The endogenous NPC1L1 expression increased and mainly expressed in neurons after MCAO. Intranasal administration of Eze reduced brain infarct volume at 24 and 72 h after MCAO, with improved short and long-term neurological functions after MCAO. Eze reduced brain cholesterol levels (total cholesterol, free cholesterol and cholesteryl esters) and the number of FJC-positive neurons. The expression of phosphorylated AMPK (p-AMPK) and downstream ULK1, Beclin1, LC3BII, Bcl-2, and Bcl-xl increased, while P62 and proapoptotic Bax decreased after treatment with Eze. Pretreatment with Dorsomorphin and 3-MA reversed the beneficial effects of Eze. These findings suggest that intranasal administration of Eze plays neuroprotective role through autophagy activation after MCAO in rats. Lowered cholesterol levels and AMPK activation may act in conjunction to induce autophagy after treatment with Eze. Eze merits further investigation as a potential therapeutic agent in ischemic stroke patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cerebral vascular injury is a major component of acute brain injury. Currently, neuroprotective strategies primarily focus on the recanalization of cerebral arteries and capillaries, and the protection of insulted neurons. Hitherto, the role of vein drainage in the pathophysiology of acute brain injury has been overlooked, due to an under appreciation of the magnitude of the impact of veins in circulation. In this review, we summarize the changes in the vein morphology and functions that are known, or likely to occur related to acute brain injury, and aim to advance the therapeutic management of acute brain injury by shifting the focus from reperfusion to another term: recirculation. Recent progress in the neurobiological understanding of the vascular neural network has demonstrated that cerebral venous systems are able to respond to acute brain injury by regulating the blood flow disharmony following brain edema, blood brain barrier disruption, ischemia, and hemorrhage. With the evidence presented in this review, future clinical management of acutely brain injured patients will expand to include the recirculation concept, establishing a harmony between arterial and venous systems, in addition to the established recanalization and reperfusion strategies., (Copyright © 2015 Elsevier Inc. All rights reserved.)