Activation of peroxisome proliferator-activated receptor beta/delta (PPAR-β/δ), a nuclear receptor acting as a transcription factor, was shown to be protective in various models of neurological diseases. However, there is no information about the role of PPAR-β/δ as well as its molecular mechanisms in neonatal hypoxia-ischemia (HI). In the present study, we hypothesized that PPAR-β/δ agonist GW0742 can activate miR-17-5p, consequently inhibiting TXNIP and ASK1/p38 pathway leading to attenuation of apoptosis. Ten-day-old rat pups were subjected to right common carotid artery ligation followed by 2.5 h hypoxia. GW0742 was administered intranasally 1 and 24 h post HI. PPAR-β/δ receptor antagonist GSK3787 was administered intranasally 1 h before and 24 h after HI, antimir-17-5p and TXNIP CRISPR activation plasmid were administered intracerebroventricularly 24 and 48 h before HI, respectively. Brain infarct area measurement, neurological function tests, western blot, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Fluoro-Jade C and immunofluorescence staining were conducted. GW0742 reduced brain infarct area, brain atrophy, apoptosis, and improved neurological function at 72 h and 4 weeks post HI. Furthermore, GW0742 treatment increased PPAR-β/δ nuclear expression and miR-17-5p level and reduced TXNIP in ipsilateral hemisphere after HI, resulting in inhibition of ASK1/p38 pathway and attenuation of apoptosis. Inhibition of PPAR-β/δ receptor and miR-17-5p and activation of TXNIP reversed the protective effects. For the first time, we provide evidence that intranasal administration of PPAR-β/δ agonist GW0742 attenuated neuronal apoptosis at least in part via PPAR-β/δ/miR-17/TXNIP pathway. GW0742 could represent a therapeutic target for treatment of neonatal hypoxic ischemic encephalopathy (HIE).

DHLA treatment improved neurofunction and alleviated inflammation through the lysosome-associated membrane protein-1/CaMKII/TAK1 pathway in early brain injury after SAH. DHLA may provide a promising treatment to alleviate early brain injury after SAH.

Cardiac arrest (CA) is a well-known cause of global brain ischemia. After CA and subsequent loss of consciousness, oxygen tension starts to decline and leads to a series of cellular changes that will lead to cellular death, if not reversed immediately, with brain edema as a result. The electroencephalographic activity starts to change as well. Although increased intracranial pressure (ICP) is not a direct result of cardiac arrest, it can still occur due to hypoxic-ischemic encephalopathy induced changes in brain tissue, and is a measure of brain edema after CA and ischemic brain injury. In this review, we will discuss the pathophysiology of brain edema after CA, some available techniques, and methods to monitor brain oxygen, electroencephalography (EEG), ICP (intracranial pressure), and microdialysis on its measurement of cerebral metabolism and its usefulness both in clinical practice and possible basic science research in development. With this review, we hope to gain knowledge of the more personalized information about patient status and specifics of their brain injury, and thus facilitating the physicians’ decision making in terms of which treatments to pursue.

Endoplasmic reticulum (ER) stress is a major pathology encountered after hypoxic-ischemic (HI) injury. Accumulation of unfolded proteins triggers the unfolded protein response (UPR), resulting in the activation of pro-apoptotic cascades that lead to cell death. Here, we identified Bax inhibitor 1 (BI-1), an evolutionarily conserved protein encoded by the transmembrane BAX inhibitor motif-containing 6 (TMBIM6) gene, as a novel modulator of ER-stress-induced apoptosis after HI brain injury in a neonatal rat pup. The main objective of our study was to overexpress BI-1, via viral-mediated gene delivery of human adenoviral-TMBIM6 (Ad-TMBIM6) vector, to investigate its anti-apoptotic effects as well as to elucidate its signaling pathways in an in vivo neonatal HI rat model and in vitro oxygen-glucose deprivation (OGD) model. Ten-day-old unsexed Sprague Dawley rat pups underwent right common carotid artery ligation followed by 1.5 h of hypoxia. Rat pups injected with Ad-TMBIM6 vector, 48 h pre-HI, showed a reduction in relative infarcted area size, attenuated neuronal degeneration and improved long-term neurological outcomes. Furthermore, silencing of BI-1 or further activating the IRE1α branch of the UPR, using a CRISPR activation plasmid, was shown to reverse the protective effects of BI-1. Based on our in vivo and in vitro data, the protective effects of BI-1 are mediated via inhibition of IRE1α signaling and in part via inhibition of the second stress sensor receptor, PERK. Overall, this study showed a novel role for BI-1 and ER stress in the pathophysiology of HI and could provide a basis for BI-1 as a potential therapeutic target.

BackgroundsWhile previous meta-analysis have investigated the efficacy of cilostazol in the secondary prevention of ischemic stroke, they were criticized for their methodology, which confused the acute and chronic phases of stroke. We present a new systematic review, which differs from previous meta-analysis by distinguishing between the different phases of stroke, and includes two new randomized, controlled trials (RCTs).MethodsAll RCTs investigating the effect of cilostazol on secondary prevention of ischemic stroke were obtained. Outcomes were analyzed by Review Manager, including recurrence of cerebral infarction (ROCI), hemorrhage stroke or subarachnoid hemorrhage (HSSH), all-cause death (ACD), and modified Rankin Scale score (mRS). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessed the quality of the evidence.Results5491 patients from six studies were included in the current study. In secondary prevention of ischemic stroke in chronic phase, cilostazol was associated with a 47% reduction in ROCI (relative risk [RR] 0.53, 95% confidence interval [CI] 0.34 to 0.81, p = 0.003), while no significant difference in HSSH and ACD compared with placebo; and 71% reduction in HSSH (RR 0.29, 95% CI 0.15 to 0.56, p = 0.0002) compared with aspirin, but not in ROCI and ACD. In the secondary prevention of ischemic stroke in acute phase, cilostazol did not show any effect in the ROCI, HSSH, ACD and mRS compared to placebo or aspirin. The quality of the evidence from chronic phase was high or moderate, and those from acute phase were moderate or low when analyzed by GRADE approach.ConclusionCilostazol provided a protective effect in the secondary prevention of the chronic phase of ischemic stroke.