No abstract

Glycine is a simple nonessential amino acid known to have neuroprotective properties. Treatment with glycine results in reduced infarct volume of the brain, neurologic function scores, and neuronal and microglial death in ischemic stroke injury. Neuroinflammation has been considered a major contributor to cerebral ischemia–induced brain damage. However, the role of glycine in neuroinflammation following ischemic stroke is unclear. The present study aimed to determine whether neuroinflammation is involved in the neuroprotective effects of glycine in cerebral ischemia injury. Ischemic stroke promotes M1 microglial polarization. Interestingly, we found that the injection of glycine in rats after injury can inhibit ischemia-induced inflammation and promote M2 microglial polarization in vivo (Sprague–Dawley rats) and in vitro (cortical microglia and BV-2 cells). We show that glycine suppresses Hif-1α by inhibiting the upregulation of NF-κB p65 after ischemia-reperfusion injury, resulting in the inhibition of proinflammatory activity. The activation of AKT mediates the inhibition of NF-κB p65/Hif-1α signaling by glycine. Moreover, we confirm that glycine-regulated AKT activation is mediated by the inhibition of PTEN in a PTEN depletion cell line, U251 cells. Glycine modulates microglial polarization after ischemic stroke, which indirectly inhibits ischemia-induced neuronal death and functional recovery. Taken together, our findings provide a new understanding of glycine in neuroprotection by inhibiting M1 microglial polarization and promoting anti-inflammation by suppressing NF-κB p65/Hif-1α signaling.

Bisperoxovanadium (pyridine-2-carboxyl) [bpV(pic)] is a commercially available PTEN inhibitor. Previous studies from us and others have shown that bpV(pic) confers neuroprotection in cerebral ischemia injury. We set up to determine whether ERK 1/2 activation plays a role in bpV(pic)-induced neuroprotective effect in cerebral ischemia injury. We found that the phosphorylation levels of Akt (p-AKT) and ERK1/2 (p-ERK 1/2) were down-regulated after cerebral ischemia–reperfusion injury. The injection of bpV(pic) after injury not only increased the level of p-AKT but also the level of p-ERK 1/2. While the inhibition of PTEN mediated the up-regulatation of p-AKT and p-ERK 1/2 by bpV(pic). Interestingly, the ERK 1/2 activation induced by bpV(pic) was also independent of the inhibition of PTEN. Our results indicate that bpV(pic) protects against OGD-induced neuronal death and promotes the functional recovery of stroke animals through PTEN inhibition and ERK 1/2 activation, respectively. This study suggests that the effect of bpV(pic) on ERK 1/2 signaling should be considered while using bpV(pic) as a PTEN inhibitor.Electronic supplementary materialThe online version of this article (10.1007/s11064-018-2558-z) contains supplementary material, which is available to authorized users.

Ischemic stroke causes the depletion of energy and induce excitotoxicity and neuroinflammation in the brain that results from thrombotic blockage. Neuroinflammation occurs initially depending on activated resident microglia that has the same function as the macrophage. Activated microglia participates in the neuroinflammatory process by phagocytosing the injured brain cells and producing the pro-and anti-inflammatory mediators. In this review, the authors present an overview of the role of microglia in mediating neuroinflammation in ischemic stroke. Key words:Microglia, ischemic stroke, neuroinflammation ABSTRACT Topic: StrokeThis is an open access article distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Neuroinflammation is a secondary response following ischemia stroke. Arginine is a non-essential amino acid that has been shown to inhibit acute inflammatory reaction. In this study we show that arginine treatment decreases neuronal death after rat cerebral ischemia/reperfusion (I/R) injury and improves functional recovery of stroke animals. We also show that arginine suppresses inflammatory response in the ischemic brain tissue and in the cultured microglia after OGD insult. We further provide evidence that the levels of HIF-1α and LDHA are increased after rat I/R injury and that arginine treatment prevents the elevation of HIF-1α and LDHA after I/R injury. Arginine inhibits inflammatory response through suppression of HIF-1α and LDHA in the rat ischemic brain tissue and in the cultured microglia following OGD insult, and protects against ischemic neuron death after rat I/R injury by attenuating HIF-1α/LDHA-mediated inflammatory response. Together, these results indicate a possibility that arginine-induced neuroprotective effect may be through the suppression of HIF-1α/LDHA-mediated inflammatory response in microglia after cerebral ischemia injury.

Glioblastoma (GBM) is the most aggressive glioma in the brain. Recurrence of GBM is almost inevitable within a short term after tumor resection. In a retrospective study of 386 cases of GBM collected between 2013 and 2016, we found that recurrence of GBM mainly occurs in the deep brain regions, including the basal ganglia, thalamus, and corpus callosum. But the mechanism underlying this phenomenon is not clear. Previous studies suggest that neuroligin‐3 (NLGN3) is necessary for GBM growth. Our results show that the levels of NLGN3 in the cortex are higher than those in the deep regions in a normal human brain, and similar patterns are also found in a normal mouse brain. In contrast, NLGN3 levels in the deep brain regions of GBM patients are high. We also show that an increase in NLGN3 concentration promotes the growth of U251 cells and U87‐MG cells. Respective use of the cortex neuron culture medium (C‐NCM) and basal ganglia neuron culture medium (BG‐NCM) with DMEM to cultivate U251, U87‐MG and GBM cells isolated from patients, we found that these cells grew faster after treatment with C‐NCM and BG‐NCM in which the cells treated with C‐NCM grew faster than the ones treated with BG‐NCM group. Inhibition of NLGN3 release by ADAM10i prevents NCM‐induced cell growth. Together, this study suggests that increased levels of NLGN3 in the deep brain region under the GBM pathological circumstances may contribute to GBM recurrence in the basal ganglia, thalamus, and corpus callosum.

No abstract

PurposeTo investigate the effects of estrogen G protein-coupled receptor 30 (GPR30) agonist G1 on hippocampal neuronal apoptosis and microglial polarization in rat traumatic brain injury (TBI).MethodsMale SD rats were randomly divided into sham group, TBI + vehicle group, TBI + G1 group. Experimental moderate TBI was induced using Feeney's weigh-drop method. G1 (100μg/kg) or vehicle was intravenously injected from femoral vein at 30 min post-injury. Rats were sacrificed at 24 h after injury for detection of neuronal apoptosis and microglia polarization. Neuronal apoptosis was assayed by immunofluorescent staining of active caspase-3. M1 type microglia markers (iNOS and IL-1β) and M2 type markers (Arg1 and IL-4) were examined by immunoblotting or ELISA. Total protein level of Akt and phosphorylated Akt were assayed by immunoblotting.ResultsG1 significantly reduced active caspase-3 positive neurons in hippocampus. Meanwhile G1 increased the ratio of Arg1/iNOS. IL-1β production was decreased but IL-4 was increased after G1 treatment. G1 treatment also increased the active form of Akt.ConclusionsGPR30 agonist G1 inhibited neuronal apoptosis and favored microglia polarization to M2 type.