Propofol Reduces Inflammatory Brain Injury after Subarachnoid Hemorrhage: Involvement of PI3K/Akt Pathway.
Our previous study showed that propofol, one of the widely used anesthetic agents, can attenuate subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) via inhibiting inflammatory and oxidative reaction. However, it is perplexing whether propofol attenuates inflammatory and oxidative reaction through modulating PI3K/Akt pathway. The present study investigated whether PI3K/Akt pathway is involved in propofol's anti-inflammation, antioxidation, and neuroprotection against SAH-induced EBI.
Adult Sprague-Dawley rats underwent SAH and received treatment with propofol or vehicle after 2 and 12 hours of SAH. LY294002 was injected intracerebroventricularly to selectively inhibit PI3K/Akt signaling. Mortality, SAH grading, neurological scores, brain water content, evans blue extravasation, myeloperoxidase, malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured 24 hours after SAH. Immunoreactivity of p-Akt, t-Akt, nuclear factor- kappa B (NF-κB) p65, nuclear factor erythroid-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase (NQO1), and cyclooxygenase-2 (COX-2) in rat brain was determined by western blot. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rat brain were examined by ELISA.
Propofol significantly reduces neurological dysfunction, BBB permeability, brain edema, inflammation, and oxidative stress, all of which were reversed by LY294002. Propofol significantly upregulates the immunoreactivity of p-Akt, Nrf2, and NQO1, all of which were abolished by LY294002. Propofol significantly downregulates the overexpression of NF-κB p65, COX-2, TNF-α, and IL-1β, all of which were inhibited by LY294002.
These results suggest that propofol attenuates SAH-induced EBI by inhibiting inflammatory reaction and oxidative stress, which might be associated with the activation of PI3K/Akt signaling pathway.
Zhang HB
，Tu XK
，Chen Q
，Shi SS
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Activation of GPR30 with G1 attenuates neuronal apoptosis via src/EGFR/stat3 signaling pathway after subarachnoid hemorrhage in male rats.
Neuron apoptosis plays a vital role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies showed that the activation of G protein-coupled receptor 30 (GPR30) with GPR30 agonist G1 was anti-apoptotic after experimental trauma brain injury and global cerebral ischemia in male rats or mice. However, the role of GPR30 activation with G1 has not been clarified in SAH. The aim of this study was to investigate the anti-apoptotic effect of GPR30 activation and the underlying mechanism of src/EGFR/stat3 signaling pathway in a male rat model of SAH.
A total of 215 male rats and 18 female rats were used. SAH was induced by intravascular perforation. G1 was administrated intravenously 1 h after SAH. For mechanism study, the GPR30 antagonist G15 or epidermal growth factor receptor (EGFR) antagonist AG1478 was administrated intravenously 1 h before SAH, small interfering ribonucleic acid (siRNA) for GPR30 and EGFR were administered intracerebroventricularly 48 h before SAH. Post-SAH assessments included SAH Grade, neurological deficits, western blot, terminal deoxynucleotidyl transferase dUTP-biotin nick end labeling (TUNEL) staining, Fluoro-Jade C (FJC) staining, Nissl staining and immunofluorescence.
The expression of endogenous GPR30 in male rats was increased at 3 h and peaked at 24 h after SAH, which mainly co-localized with neurons, but there was no significant increase in intact female rats at 24 h after SAH. The G1 post-treatment significantly reduced the short-term and long-term neurological deficit as well as neuronal apoptosis in male rats, but it did not significantly improve the short-term outcome of intact female rats. Mechanistic studies indicated that G15 or GPR30 siRNA and AG1478 or EGFR siRNA reversed the anti-neuronal apoptosis effects of G1 and its effects on protein expressions of src/EGFR/stat3 signaling pathway.
G1 reduced EBI through attenuating neuronal apoptosis after SAH in male rats, partly via activating src/EGFR/stat3/signaling pathway. G1 may provide a promising therapeutic strategy for SAH patients.
Peng J
，Zuo Y
，Huang L
，Okada T
，Liu S
，Zuo G
，Zhang G
，Tang J
，Xia Y
，Zhang JH
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ResearchGate
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