Abstract
To investigate whether the neuroprotective effect of TSA on cerebral ischemia reperfusion injury is mediated by the activation of Akt/GSK-3β signaling pathway. 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. 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. 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.
Highlights
Stroke, one of the serious diseases that threaten human health, is a pathological condition due to the occlusion of blood vessels which providing oxygen and essential nutrients to the brain, and it is characterized with high incidence, high morbidity and high mortality[1]
Recent studies have shown that the gene expression in ischemic stroke is abnormal, and acetylation is one of important mechanisms for gene transcription, regulation and expression, which mainly consists of histone acetylase (HAT) and histone deacetylase (HDAC)[4,5]
The results of this study showed that TSA preconditioning can increase the expression of p-Akt, p-GSK-3β and the neuroprotection induced by TSA pretreatment can be blocked by LY294002, which indicating that the Akt/ GSK-3β pathways involved in cerebral ischemia reperfusion injury, and the neuroprotective effect may be partly due to reducing oxidative stress, inflammation and apoptosis
Summary
One of the serious diseases that threaten human health, is a pathological condition due to the occlusion of blood vessels which providing oxygen and essential nutrients to the brain, and it is characterized with high incidence, high morbidity and high mortality[1]. Current clinical treatment for ischemic stroke is regaining blood supplies to the ischemic brain tissue, but more and more clinical cases show that this treatment may alleviate the situation of cerebral ischemia in a short time, but it is very limit for improvement of neurological function, and even aggravate the injury, this phenomenon is called cerebral ischemia reperfusion injury (CIRI)[3]. Recent studies have shown that the gene expression in ischemic stroke is abnormal, and acetylation is one of important mechanisms for gene transcription, regulation and expression, which mainly consists of histone acetylase (HAT) and histone deacetylase (HDAC)[4,5]. HDAC plays a significant part in epigenetic related signaling pathways which can participate in various life activities by regulating the balance of acetylation and deacetylation by histone and non-histones, including cell growth, differentiation, death, as well as the interactions and inflammations between cells and interstitial[6]
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