Ceftriaxone alleviates early brain injury after subarachnoid hemorrhage by increasing excitatory amino acid transporter 2 expression via the PI3K/Akt/NF-κB signaling pathway.

Early brain injury (EBI) after subarachnoid hemorrhage (SAH) is characterized by a reduction in excitatory amino acid transporter 2 (EAAT2) expression and severe amino acid excitotoxicity. The aim of this study was to explore the neuroprotective effect of ceftriaxone (CEF), a potent compound that up-regulates EAAT2, against EBI and the potential mechanisms using in vitro experiments and a rat model of SAH. Intracisternal treatment with CEF significantly improved neurological outcomes and alleviated extracellular glutamate accumulation after SAH. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining and Western blot analysis of cleaved caspase 3 showed that CEF decreased hippocampal neuronal apoptosis following SAH. Immunofluorescent staining and Western blotting revealed that CEF significantly reversed the down-regulation of EAAT2 expression following SAH. In Morris water maze (MWM) tests, CEF remarkably ameliorated the SAH-induced cognitive dysfunction in spatial learning memory and reference memory. CEF promoted the nuclear translocation of p65 as well as the activation of Akt in hippocampal astrocytes in vitro and in vivo. These findings suggest that CEF may exert significant protective effects against EBI following SAH by modulating the PI3K/Akt/NF-κB signaling pathway.

Feng D ，Wang W ，Dong Y ，Wu L ，Huang J ，Ma Y ，Zhang Z ，Wu S ，Gao G ，Qin H ... -  《-》

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome.

Shao A ，Wu H ，Hong Y ，Tu S ，Sun X ，Wu Q ，Zhao Q ，Zhang J ，Sheng J ... -  《-》

Standardized Ginkgo biloba extract EGb 761® attenuates early brain injury following subarachnoid hemorrhage via suppressing neuronal apoptosis through the activation of Akt signaling.

Early brain injury (EBI) plays a critical role in determining the outcome of subarachnoid hemorrhage (SAH). The present study was designed to investigate the role of EGb 761, a standardized extract of Ginkgo biloba, in SAH-induced EBI and to explore its potential mechanism of action. A rat SAH model was established by the endovascular perforation process. Doses of 10, 50 and 100 mg/kg EGb 761 were injected intraperitoneally 2 h after SAH was induced. Mortality, SAH grade, neurological score and brain water content were measured 24 h after SAH was induced. A Western blot assay was performed to assess the expression of the apoptosis-related proteins Bax, Bcl-2, cleaved caspase-3, Akt and phosphorylated Akt (p-Akt). Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and neuronal nuclei (NeuN) double immunofluorescence staining were used to detect apoptotic neurons. Animals suffered from serious neurological deficits and increased brain water content after induction of SAH. Rats treated with EGb 761 experienced dose-dependent attenuation of neurological dysfunction and decreased brain water content. In addition, EGb 761 significantly activated Akt signaling accompanied by increased Bcl-2 levels and decreased expression of Bax and cleaved caspase-3. Moreover, EGb 761 decreased the number of TUNEL/NeuN-positive cells in a dose-dependent manner. However, all the beneficial effects of EGb 761 for SAH were abolished by the Akt inhibitor MK2206. Our results indicated that EGb 761 could ameliorate SAH-induced EBI and that the neuroprotective effects of EGb 761 against SAH were exerted via suppression of neuronal apoptosis through activation of the Akt pathway.

Yu T ，Fan Y ，Xu Y ，Xu L ，Xu G ，Cao F ，Jiang H ... -  《-》

Resveratrol prevents neuronal apoptosis in an early brain injury model.

Resveratrol has been shown to attenuate cerebral vasospasm after subarachnoid hemorrhage (SAH); however, no study has explored its neuroprotective effect in early brain injury (EBI) after experimental SAH. The aim of this study was to evaluate the antiapoptotic function of resveratrol in EBI and its relationship with the PI3K/Akt survival pathway. Experimental SAH was induced in adult male rats by prechiasmatic cistern injection. Control and SAH rats were divided into six groups and treated with low (20 mg/kg) or high (60 mg/kg) concentrations of resveratrol with or without LY294002 cotreatment. Brain samples of the rats were analyzed by immunohistochemistry, immunofluorescence staining, Western blotting, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assays. High-concentration but not low-concentration resveratrol treatment in SAH rats led to a significant increase in phosphorylated Akt (p-Akt) protein levels compared with SAH rats without treatment. In addition, p-Akt-positive cells mainly colocalized with NeuN-positive cells. Neuronal apoptosis in SAH rat brain was attenuated by high-concentration resveratrol treatment. The antiapoptotic effect of resveratrol in SAH rats could be partially abrogated by the PI3K/Akt signaling inhibitor LY294002. Our results show that resveratrol has an antiapoptotic effect in EBI and that resveratrol might act through the PI3K/Akt signaling pathway.

Zhou XM ，Zhou ML ，Zhang XS ，Zhuang Z ，Li T ，Shi JX ，Zhang X ... -  《-》

Baincalein alleviates early brain injury after experimental subarachnoid hemorrhage in rats: possible involvement of TLR4/NF-κB-mediated inflammatory pathway.

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) largely contributes to unfavorable outcomes. Hence, effective therapeutic strategies targeting on EBI have recently become a major goal in the treatment of SAH patients. Baicalein is a flavonoid that has been shown to offer neuroprotection in kinds of brain injury models. This study investigated the effects of baicalein on EBI in rats following SAH. SAH was inducted in male Sprauge-Dawley rats by injection of fresh non-heparinized arterial blood into the prechiasmatic cistern. Baicalein (30 or 100 mg/kg) or vehicle were administrated 30 min after injury. Neurological deficit, brain edema, blood-brain barrier (BBB) permeability and neural cell apoptosis were assessed. To explore the further mechanisms, the change of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) signaling pathway and the levels of apoptosis associated proteins were also examined. Our study showed that treatment with baicalein (30 mg/kg) significantly improved neurological function at 24h after SAH and reduced brain edema at both 24h and 72 h after SAH. Baicalein also significantly reduced neural cell death, BBB permeability. These changes were associated with the remarkable reductions of TLR4 expression, IκB-α degradation, NF-κB translocation to nucleus, as well as the expressions of matrix metalloproteinase-9, tight junctions protein, interleukin-1β and tumor necrosis factor- ɑ. These findings suggest that baicalein may ameliorate EBI after SAH potentially via inhibition of inflammation-related pathway.

Wang CX ，Xie GB ，Zhou CH ，Zhang XS ，Li T ，Xu JG ，Li N ，Ding K ，Hang CH ，Shi JX ，Zhou ML ... -  《-》