SirT1 mediates hyperbaric oxygen preconditioning-induced ischemic tolerance in rat brain

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Hyperbaric oxygen preconditioning (HBO-PC) is known to induce tolerance to cerebral ischemia/reperfusion (I/R) injury.
• The role of SirT1, a class III histone deacetylase, in HBO-PC-mediated neuroprotection remains to be elucidated.

Purpose of the Study:

• To investigate the involvement of SirT1 in the neuroprotective effects of HBO-PC in animal and cell culture models of cerebral ischemia.
• To explore the molecular mechanisms underlying HBO-PC-induced neuroprotection mediated by SirT1.

Main Methods:

• Rats underwent middle cerebral artery occlusion after HBO-PC treatment.
• Primary cortical neurons were subjected to oxygen-glucose deprivation (OGD) followed by HBO-PC.
• SirT1 expression was modulated using inhibitors, activators, and siRNA.
• Neurobehavioral scores, infarct volume, cell morphology, cell viability, and apoptosis markers (Bcl-2, cleaved caspase 3) were assessed.

Main Results:

• HBO-PC increased SirT1 protein and mRNA expression, improved neurobehavioral scores, reduced infarct volume, and enhanced morphology post-I/R.
• Neuroprotection by HBO-PC was diminished by SirT1 inhibition/knockdown and mimicked by SirT1 activation.
• In neuronal cultures, HBO-PC enhanced SirT1 expression, improved cell viability, and reduced cell death markers after OGD/re-oxygenation.
• SirT1 activation by HBO-PC led to increased Bcl-2 and decreased cleaved caspase 3, indicating apoptosis inhibition.

Conclusions:

• SirT1 plays a critical role in mediating the neuroprotective effects of HBO-PC against cerebral I/R injury.
• HBO-PC confers tolerance to cerebral I/R by upregulating SirT1, which subsequently inhibits apoptosis.
• Targeting the SirT1 pathway presents a promising therapeutic avenue for managing ischemic stroke.