Cole Sorrels

Introduction: Subarachnoid Hemorrhage (SAH) is a debilitating and frequently lethal form of stroke that accounts for 5 to 10% of all stroke cases in the United States annually.^1,2,3 Early brain injury (EBI) is thought to be the primary cause of disability and mortality in SAH patients and occurs within the first 24-72 hours of stroke onset.^4,5 While progress has been made for SAH treatment and diagnosis, there is currently no targeted therapy for SAH-induced EBI.⁶ The PI3K/Akt signaling pathway is well known as a major upstream element that plays a critical role in controlling the balance between cell survival and cell damage.⁵ Propofol, a widely used anesthetic agent, has been shown to attenuate SAH-induced early brain injury by inhibiting inflammatory and oxidative reactions, possibly through the PI3K/Akt signaling pathway.^4,5 It is unknown whether propofol can achieve these effects through the modulation of the PI3K/Akt pathway and what the mechanism is for propofol’s anti-inflammatory effects regarding SAH.⁵ Methods: In the first reviewed study, adult Sprague-Dawley rats underwent SAH and received treatment with propofol or a vehicle after 2 and 12 hours of SAH.⁵ LY294002 was injected intracerebroventricularly to selectively inhibit PI3K/Akt signaling.⁵ Mortality, SAH grading, neurological scores, and brain water content were measured 24 hours after SAH.⁵ Various oxidative and inflammatory mediators were measured via western blot and ELISA analysis.⁵ The second study was performed with similar parameters to the first but instead observed cerebral ischemic injury rather than SAH.⁷ Results: Both studies showed improvements in neurological scores and blood-brain barrier integrity, reduced cerebral water content, upregulated anti-inflammatory mediators, and downregulated proinflammatory mediators. The anti-inflammatory mediators that were upregulated were IL-10 and IL-4.^5,7 The pro-inflammatory mediators that were downregulated were TNF-a, IL-1b, and IL-6.^5,7 Propofol’s attenuative effects on SAH-EBI and ischemic injury were reversed in the LY294002, PI3K/Akt inhibitor, group.^5,7 There was no significant change in SAH-induced rats’ mortality due to propofol administration.⁵ Conclusion: These results suggest propofol attenuates SAH-induced EBI by inhibiting inflammatory reaction and oxidative stress, which may be associated with PI3K/Akt pathway activation.⁵ While mortality wasn’t reduced due to propofol administration, it was shown that propofol downregulated the expression of inflammatory mediators such as TNF-a, IL-1b, and IL-6, while upregulating anti-inflammatory mediators such as IL-10 and IL-4.^5,7 These results suggest that the PI3K/Akt pathway might be a promising therapeutic target and propofol might be a therapeutic agent for the treatment of SAH in future to alleviate inflammatory brain damage.

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2. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Statistics Committee and Stroke Statistics Subcommittee: Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation 2017; 135:e146–603
3. Wu LY, Enkhjargal B, Xie ZY, et al. Recombinant OX40 attenuates neuronal apoptosis through OX40-OX40L/PI3K/AKT signaling pathway following subarachnoid hemorrhage in rats. Exp Neurol. 2020;326:113179. doi:10.1016/j.expneurol.2020.113179
4. Modi S, Shah K, Schultz L, Tahir R, Affan M, Varelas P. Cost of hospitalization for aneurysmal subarachnoid hemorrhage in the United States. Clin Neurol Neurosurg. 2019;182:167-170. doi:10.1016/j.clineuro.2019.05.018
5. Zhang HB, Tu XK, Chen Q, Shi SS. Propofol Reduces Inflammatory Brain Injury after Subarachnoid Hemorrhage: Involvement of PI3K/Akt Pathway. J Stroke Cerebrovasc Dis. 2019;28(12):104375. doi:10.1016/j.jstrokecerebrovasdis.2019.104375
6. Lin F, Li R, Tu WJ, et al. An Update on Antioxidative Stress Therapy Research for Early Brain Injury After Subarachnoid Hemorrhage. Front Aging Neurosci. 2021;13:772036. Published 2021 Dec 6. doi:10.3389/fnagi.2021.772036
7. Chen Y, Li Z. Protective Effects of Propofol on Rats with Cerebral Ischemia-Reperfusion Injury Via the PI3K/Akt Pathway. J Mol Neurosci. 2021;71(4):810-820. doi:10.1007/s12031-020-01703-8