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Insulin-like growth factor 1 (IGF-1) has neuroprotective actions, including vasodilatory, anti-inflammatory, and antithrombotic effects, following ischemic stroke. However, the molecular mechanisms underlying the neuroprotective effects of IGF-1 following ischemic stroke remain unknown. Therefore, in the present study, we investigated whether IGF-1 exerted its neuroprotective effects by regulating the Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT cascade, following ischemic stroke. In the in vitro study, we exposed cultured PC12 and SH-5YSY cells, and cortical primary neurons, to oxygen-glucose deprivation. Cell viability was measured using CCK-8 assay. In the in vivo study, Sprague-Dawley rats were subjected to middle cerebral artery occlusion. Neurological function was assessed using a modified neurologic scoring system and the modified neurological severity score (mNSS) test, brain edema was detected by brain water content measurement, infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis were evaluated by TUNEL/NeuN double staining, HE and Nissl staining, and immunohistochemistry staining for NeuN. Finally, western blot analysis was used to measure the level of IGF-1 in vivo and levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and reduced neurological deficits, brain water content, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were blocked by an inhibitor of the PI3K/AKT cascade, LY294002. LY294002 treatment not only downregulated PI3K and p-AKT, but YAP/TAZ as well, leading to aggravation of neurological dysfunction and worsening of brain damage. Our findings indicate that the neuroprotective effects of IGF-1 are, at least in part mediated by upregulation of YAP/TAZ via activation of the PI3K/AKT cascade following cerebral ischemic stroke.

Subarachnoid hemorrhage (SAH) is a subtype of stroke with high mortality and morbidity due to the lack of effective therapy. Atorvastatin has been reported to alleviate early brain injury (EBI) following subarachnoid hemorrhage (SAH) via reducing reactive oxygen species, antiapoptosis, regulated autophagy, and neuroinflammation. Which was the related to the pyroptosis? Pyroptosis can be defined as a highly specific inflammatory programmed cell death, distinct from classical apoptosis and necrosis. However, the precise role of pyroptosis in atorvastatin-mediated neuroprotection following SAH has not been confirmed. The present study aimed to investigate the neuroprotection and potential molecular mechanisms of atorvastatin in the SAH-induced EBI via regulating neural pyroptosis using the filament perforation model of SAH in male C57BL/6 mice, and the hemin-induced neuron damage model in HT-22. Atorvastatin or vehicle was administrated 2 h after SAH and hemin-induced neuron damage. The mortality, neurological score, brain water content, and neuronal death were evaluated. The results show that the atorvastatin treatment markedly increased survival rate, neurological score, greater survival of neurons, downregulated the protein expression of NLRP1, cleaved caspase-1, interleukin-1β (IL-1β), and IL-18, which indicated that atorvastatin-inhibited pyroptosis and neuroinflammation, ameliorated neuron death in vivo/vitro subjected to SAH. Taken together, this study demonstrates that atorvastatin improved the neurological outcome in rats and reduced the neuron death by against neural pyroptosis and neuroinflammation.

Tetramethylpyrazine (TMP) has been studied in depth and is widely used in the treatment of many kinds of diseases in China. However, whether it has neuroprotective effects on cerebral ischemia remains unclear. An ischemia/reperfusion (I/R) injury animal model was established via middle cerebral artery occlusion in this study. We set several different groups in which the rats were performed in different ways to explore the effects of TMP on blood-brainbarrier (BBB) disruption and determine whether TMP relieved BBB disruption through blocking the JAK/STAT signaling pathway. Our results showed that TMP could reduce the neurological functional loss, decrease the brain edema and BBB permeability, as well as increase the expression of tight junction proteins via inhibiting the activation of JAK/STAT signaling pathway. Overall, we demonstrated that TMP promoted neurological recovery after I/R injury via restoring the integrity and function of BBB.

Ischemia/reperfusion (I/R) injuries commonly lead to breakdown of the blood-brain barrier (BBB). Restoration of the BBB can relieve neurologic damage caused by I/R injuries. The Hippo/YAP signaling pathway mediates cell proliferation, regulated cell death, and differentiation in various organisms and has been shown to participate in the restoration of the heart after I/R. In this study, we investigated whether the Hippo/YAP pathway plays a role in I/R injury in brain, especially in regard to I/R-induced BBB breakdown. The results of our study indicate that I/R injury led to an overall decrease in activity of the core proteins, YAP and TAZ, over a 24-h period. The most dramatic change was observed 1.5 h after reperfusion. In rats that underwent 1.5 h of reperfusion, intraperitoneal injection of YAP agonist dexamethasone activated YAP and TAZ and led to improved neurologic function, smaller brain infarct sizes, increased levels of tight junction proteins, decreased BBB permeability, decreased cerebral edema, and less apoptosis. Our results suggest that YAP exerts neuroprotective effects on the damaged brain that are likely related to restoration of the BBB.

Brain microvascular endothelial cells form the interface between nervous tissue and circulating blood, and regulate central nervous system homeostasis. Brain microvascular endothelial cells differ from peripheral endothelial cells with regards expression of specific ion transporters and receptors, and contain fewer fenestrations and pinocytotic vesicles. Brain microvascular endothelial cells also synthesize several factors that influence blood vessel function. This review describes the morphological characteristics and functions of brain microvascular endothelial cells, and summarizes current knowledge regarding changes in brain microvascular endothelial cells during stroke progression and therapies. Future studies should focus on identifying mechanisms underlying such changes and developing possible neuroprotective therapeutic interventions.

Subarachnoid hemorrhage (SAH) results in significant nerve dysfunction, such as hemiplegia, mood disorders, cognitive and memory impairment. Currently, no clear measures can reduce brain nerve damage. The study of brain nerve protection after SAH is of great significance. We aim to evaluate the protective effects and the possible mechanism of methazolamide in C57BL/6J SAH animal model in vivo and in blood-induced primary cortical neuron (PCNs) cellular model of SAH in vitro. We demonstrate that methazolamide accelerates the recovery of neurological damage, effectively relieves cerebral edema, and improves cognitive function in SAH mice as well as offers neuroprotection in blood- or hemoglobin-treated PCNs and partially restores normal neuronal morphology. In addition, western blot analyses show obviously decreased expression of active caspase-3 in methazolamide-treated SAH mice comparing with vehicle-treated SAH animals. Furthermore, methazolamide effectively inhibits ROS production in PCNs induced by blood exposure or hemoglobin insult. However, methazolamide has no protective effects in morality, fluctuation of cerebral blood flow, SAH grade, and cerebral vasospasm of SAH mice. Given methazolamide, a potent carbonic anhydrase inhibitor, can penetrate the blood–brain barrier and has been used in clinic in the treatment of ocular conditions, it provides potential as a novel therapy for SAH.

Cell-surface receptors provide potential targets for the translation of bench-side findings into therapeutic strategies; however, this approach for the treatment of stroke is disappointing, at least partially due to an incomplete understanding of the targeted factors. Previous studies of oncostatin M (OSM), a member of the gp130 cytokine family, have been limited, as mouse models alone may not strongly resemble the human condition enough. In addition, the precise function of OSM in the CNS remains unclear. Here, we report that human OSM is neuroprotective in vivo and in vitro by recruiting OSMRβ in the setting of ischemic stroke. Using gain- and loss-of-function approaches, we demonstrated that decreased neuronal OSMRβ expression results in deteriorated stroke outcomes but that OSMR β overexpression in neurons is cerebroprotective. Moreover, administering recombinant human OSM to mice before the onset of I/R showed that human OSM can be protective in rodent models of ischemic stroke. Mechanistically, OSM/OSMRβ activate the JAK2/STAT3 prosurvival signaling pathway. Collectively, these data support that human OSM may represent a promising drug candidate for stroke treatment. SIGNIFICANCE STATEMENT OSM, a member of the gp130 cytokine family, regulates neuronal function and survival. OSM engages a second receptor, either LIFRα or OSMRβ, before recruiting gp130. However, it is not clear whether OSM/OSMRβ signaling is involved in neuroprotection in the setting of ischemic stroke. Recent studies show that, compared with mouse disease models, the OSM receptor system in rats more closely resembles that in humans. In the present study, we use genetic manipulations of OSMRβ in both mouse and rat stroke models to demonstrate that OSMRβ in neurons is critical for neuronal survival during cerebral ischemic/reperfusion. Interestingly, administration of human OSM also leads to improved stroke outcomes. Therefore, OSM may represent a promising drug candidate for stroke treatment.

N-acetylserotonin (NAS) is an immediate precursor of melatonin, which we have reported is neuroprotective against ischemic injury. Here we test whether NAS is a potential neuroprotective agent in experimental models of ischemic injury. We demonstrate that NAS inhibits cell death induced by oxygen–glucose deprivation or H2O2in primary cerebrocortical neurons and primary hippocampal neuronsin vitro, and organotypic hippocampal slice culturesex vivoand reduces hypoxia/ischemia injury in the middle cerebral artery occlusion mouse model of cerebral ischemiain vivo. We find that NAS is neuroprotective by inhibiting the mitochondrial cell death pathway and the autophagic cell death pathway. The neuroprotective effects of NAS may result from the influence of mitochondrial permeability transition pore opening, mitochondrial fragmentation, and inhibition of the subsequent release of apoptogenic factors cytochromec, Smac, and apoptosis-inducing factor from mitochondria to cytoplasm, and activation of caspase-3, -9, as well as the suppression of the activation of autophagy under stress conditions by increasing LC3-II and Beclin-1 levels and decreasing p62 level. However, NAS, unlike melatonin, does not provide neuroprotection through the activation of melatonin receptor 1A. We demonstrate that NAS reaches the brain subsequent to intraperitoneal injection using liquid chromatography/mass spectrometry analysis. Given that it occurs naturally and has low toxicity, NAS, like melatonin, has potential as a novel therapy for ischemic injury.