Sirt1 Mediates Hyperbaric Oxygen Preconditioning-Induced Ischemic Tolerance in Rat Brain

Abstract

Our previous studies have shown that hyperbaric oxygen preconditioning (HBO-PC) induces tolerance to cerebral ischemia/reperfusion (I/R). This study aimed to investigate whether SirT1, a class III histone deacetylase, is involved in neuroprotection elicited by HBO-PC in animal and cell culture models of ischemia. Rats were subjected to middle cerebral artery occlusion for 120 minutes after HBO-PC (once a day for 5 days). Primary cultured cortical neurons were exposed to 2 hours of HBO-PC after 2 hours of oxygen–glucose deprivation (OGD). We showed that HBO-PC increased SirT1 protein and mRNA expression, promoted neurobehavioral score, reduced infarct volume, and improved morphology at 24 hours and 7 days after cerebral I/R. Neuroprotection of HBO-PC was attenuated by SirT1 inhibitor EX527 and SirT1 knockdown by short interfering RNA (siRNA), whereas it was mimicked by SirT1 activator resveratrol. Furthermore, HBO-PC enhanced SirT1 expression and cell viability and reduced lactate dehydrogenase release 24 hours after OGD/re-oxygenation. The neuroprotective effect of HBO-PC was emulated through upregulating SirT1 and, reversely, attenuated through downregulating SirT1. The modulation of SirT1 was made by adenovirus infection carrying SirT1 or SirT1 siRNA. Besides, SirT1 increased B-cell lymphoma 2 (Bcl-2) expression and decrease cleaved caspase 3. These results indicate that SirT1 mediates HBO-PC-induced tolerance to cerebral I/R through inhibition of apoptosis.

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

“…Resveratrol-mediated neuroprotection was lost in the presence of sirtinol, confirming a role for SIRT1 in resveratrolmediated ischemic neuroprotection [38,39]. Using a different model of preconditioning, Yan et al [40] demonstrated that hyperbaric oxygen preconditioning increased SIRT1 protein [38] expression and that inhibition of SIRT1 deacetylase activity with EX527 blocked hyperbaric oxygen preconditioning neuroprotection against MCAO-mediated damage. It is interesting to note that transgenic mice overexpressing neuronalspecific SIRT1 are not protected against ischemic damage, suggesting that other signaling pathways may work in conjunction with SIRT1 for the induction of ischemic tolerance [41].…”

Posttreatment with 11-Keto-β-Boswellic Acid Ameliorates Cerebral Ischemia–Reperfusion Injury: Nrf2/HO-1 Pathway as a Potential Mechanism

“…Under chloral hydrate anesthesia, focal cerebral ischemia was performed using the method of right MCAO with an intraluminal filament as described previously [13]. Cerebral blood flow (CBF) was monitored using laser Doppler flowmetry (Perimed AB, PeriFlux System 5000, Stockholm, Sweden) in the ipsilateral cortex (2 mm posterior and 5 mm lateral to the bregma).…”

Epigenetic Mechanisms in Cerebral Ischemia

“…The upregulation of the HDAC SIRT1 has been described to confer protection in stroke. 72 However, histone acetylation levels are not considered in this study and SIRT1 is known to have a wide range of non-histone targets 73 that constitute potential mediators of the protective effect. Interestingly, in a genome-wide association study for ischemic stroke, carried out in humans by the International Stroke Genetics Consortium and the Welcome Trust Case Control Consortium2, a new association has been identified between HDAC 9 and large vessel stroke, one of the brain infarct subtypes.…”