The role of histone deacetylase inhibitors in regulation of Akt/GSK-3β signaling pathway in mice following transient focal cerebral ischemia

Abstract

Purpose: To investigate whether the neuroprotective effect of TSA on cerebral ischemia reperfusion injury is mediated by the activation of Akt/GSK-3β signaling pathway. Methods: Mice were randomly divided into four groups (n=15): sham group (S); ischemia reperfusion group (IR); ischemia reperfusion and pretreated with TSA group (IR+T); ischemia reperfusion and pretreated with TSA and LY294002 group (IR+T+L). The model of cerebral ischemia reperfusion was established by 1h of MCAO following 24h of reperfusion. TSA (5mg/ kg) was intraperitoneally given for 3 days before MCAO, Akt inhibitor, LY294002 (15 nmol/kg) was injected by tail vein 30 min before the MCAO. Results: TSA significantly increased the expression of p-Akt, p-GSK-3β proteins and the levels of SOD, Bcl-2, reduced the infarct volume and the levels of MDA, ROS, TNF-α, IL-1β, Bax, Caspase-3, TUNEL and attenuated neurological deficit in mice with transient MCAO, LY294002 weakened such effect of TSA dramatically. Conclusions: TSA could significantly decrease the neurological deficit and reduce the cerebral infarct volume, oxidative stress, inflammation, as well as apoptosis during cerebral ischemia reperfusion injury, which was achieved by activation of the Akt/GSK-3β signaling pathway.

Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In Vitro

“…Focal cerebral ischemia was induced by MCAO in the mice using a silk plug, as previously described [31]. Eight weeks after diabetes induction, the mice were deeply anaesthetized with isoflurane, and the left external carotid artery (ECA) was exposed.…”

“…The success of the model is marked by the presence of hemiparalysis, which is heavier in the ischemic contralateral limb after the anesthesia regains. The neurological score was measured by a blinded investigator at 24 hours after MCAO according to a neurological grading scale previously described [31]: 0, asymptomatic; 1, right forelimb cannot be straightened when lifting the tail; 2, rotating to the right side when walking; 3, pour to the right side when walking; and 4, no spontaneous activity and/or level of consciousness was depressed. The mice that showed a neurological score with 1 to 4 and brains with no detectable hemorrhage were included for analysis.…”

“…Cerebral infarct volume was detected by TTC staining. The six mice of each group were sacrificed to assess the infarct volume, as described previously [31]. The brain was placed into a special slice mold for the mice brain and was cut into 2 mm thick coronal sections.…”

Melatonin protects against focal cerebral ischemia-reperfusion injury in diabetic mice by ameliorating mitochondrial impairments: involvement of the Akt-SIRT3-SOD2 signaling pathway

“…Notedly, protein kinase B (PKB, also known as Akt) is a well-established pro-survival signaling molecule resistant to oxidative damage and mitochondrial insults in the brain [27,28]. Previously, we and other scholars have demonstrated that Akt signaling activation protected the brain against CIR injury in nondiabetic animal models [29][30][31]. Sirtuin 3 (SIRT3) is the primary mitochondrial sirtuin in the brain [32].…”