SC79, the AKT Activator Protects Cerebral Ischemia in a Rat Model of Ischemia/Reperfusion Injury

Abstract

BackgroundActivation of AKT pathway attenuates brain damage and neuronal apoptosis during cerebral ischemia/reperfusion (I/R) injury. SC79 is a novel, selective and highly-efficient Akt activator. This study aimed to investigate the neuroprotective effect of SC79 against cerebral I/R injury in a rat model, and to explore the possible underlying mechanisms.Material/MethodsMale Sprague-Dawley rats received cerebral ischemia for 1 hour, followed by brain reperfusion for 0.5–24 hours. The cerebral I/R injury animal model were treated with SC79 alone or SC79 in combination with LY294002. Western blots were used to detect the levels of expression of phosphatidylinositol AKT (p-Akt), Bax, and bcl-2. Twenty-four hours after cerebral I/R, the degree of brain injury was evaluated by detecting the neurological deficit score (NDS). The infarct rate of brain tissue was observed by TTC (2, 3, 5-triphenyltetrazolium chloride) staining. TUNEL (terminal deoxynucleotidyl transferase-mediated UTP nick end labeling) staining was used to detect cell apoptosis.Resultsp-Akt was activated during early cerebral I/R at 0.5 hours, and reached the highest levels at 4 hours, then gradually decreased from 6 hours, and reached and maintained the lowest levels at 12–24 hours. Bax expression was gradually increased from 6 hours and reached the highest level at 24 hours. However, bcl-2 expression was gradually increased and reached the highest levels at 4 hours, then gradually decreased from 6 hours, and reached the lowest levels at 24 hours. Administration of SC79 decreased infarct volumes and improved neurological function significantly. LY294002 in combination with SC79 lost the capability of SC79 to resist the cerebral I/R injury. SC79 treatment alone activated p-Akt and promoted anti-apoptotic bcl-2 and inhibited anti-apoptotic Bax expression in middle cerebral artery occlusion (MCAO) mice. However, combined SC79 and LY294002 treatment abolished SC79-induced p-Akt activity, inhibited anti-apoptotic bcl-2 and promoted anti-apoptotic Bax expression in MCAO mice. Furthermore, SC79 treatment alone attenuated apoptotic neuronal cell death, but abolished this effect in SC79 in combination with LY294002 treated groups.ConclusionsSC79 significantly increased Akt activation and reduced infarct volume and subsequently improved neurological function in ischemic brain after cerebral I/R injury in rats. These findings suggested that SC79 may be as a neuroprotective drug to be potentially used in the clinic.

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

“…The analysis of Cyt c phosphorylation state post-treatment resulted in complete dephosphorylation of Cyt c in the presence of wortmannin, suggesting a potential role for Akt in mediating this pathway. Interestingly, several studies have shown that Akt activator SC79 is an effective treatment for cerebral ischemia/reperfusion injury in animal models [ 54 , 55 , 56 ]. We and others have shown that activated, phosphorylated Akt translocates to the mitochondrial IMS where Cyt c resides [ 34 , 35 , 36 ].…”

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“…The tissue sections were stained histochemically using hematoxylin and eosin (H&E) (Beyotime Biotech., Shanghai, China) and were examined by light microscopy, as previously described [17]. Photomicrographs of the tissue sections were taken using a light microscope (Olympus, Tokyo, Japan) at a magnification of ×400.…”

Magnesium sulfate ameliorates carbon monoxide‑induced cerebral injury in male rats

“…Activated Akt influences a number of factors involved in apoptosis, either by transcription regulation or direct phosphorylation, yielding favorable effects against ischemia-induced apoptosis. Thus, chemicals capable of inducing Akt expression/activity may be used in the treatment of I/R injury (2,32–35).…”