Ferulic acid regulates the AKT/GSK-3β/CRMP-2 signaling pathway in a middle cerebral artery occlusion animal model

Abstract

Ferulic acid, a component of the plants Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort, exerts a neuroprotective effect by regulating various signaling pathways. This study showed that ferulic acid treatment prevents the injury-induced increase of collapsin response mediator protein 2 (CRMP-2) in focal cerebral ischemia. Glycogen synthase kinase-3β (GSK-3β) regulates CRMP-2 function through phosphorylation of CRMP-2. Moreover, the pro-apoptotic activity of GSK-3β is inactivated by phosphorylation by Akt. This study investigated whether ferulic acid modulates the expression of CRMP-2 and its upstream targets, Akt and GSK-3β, in focal cerebral ischemia. Male rats were treated immediately with ferulic acid (100 mg/kg, i.v.) or vehicle after middle cerebral artery occlusion (MCAO), and then cerebral cortices were collected 24 hr after MCAO. MCAO resulted in decreased levels of phospho-Akt and phospho-GSK-3β, while ferulic acid treatment prevented the decrease in the levels of these proteins. Moreover, phospho-CRMP-2 and CRMP-2 levels increased during MCAO, whereas ferulic acid attenuated these injury-induced increases. These results demonstrate that ferulic acid regulates the Akt/GSK-3β/CRMP-2 signaling pathway in focal cerebral ischemic injury, thereby protecting against brain injury.

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“…Moreover, neuroprotective agents alleviate MCAO-induced decreases in phosphorylation of Akt and its down-stream targets [50][51][52][53]. MCAO clearly results in decreased levels of phospho-Akt and phospho-GSK-3β and neuroprotective agents attenuate the decreases in the levels of these proteins [50,53]. The present study showed that focal cerebral ischemia significantly reduces phospho-Akt and phospho-GSK-3β expressions in cerebral cortex.…”

“…Our previous studies demonstrated that MCAO decreases Akt phosphorylation and consecutively reduces phosphorylation of its down-stream targets such as Bad, forkhead transcription factors, and GSK-3 beta [50][51][52][53]. Moreover, neuroprotective agents alleviate MCAO-induced decreases in phosphorylation of Akt and its down-stream targets [50][51][52][53]. MCAO clearly results in decreased levels of phospho-Akt and phospho-GSK-3β and neuroprotective agents attenuate the decreases in the levels of these proteins [50,53].…”

“…It also contributes to neuronal migration and survival [46][47][48][49]. Our previous studies demonstrated that MCAO decreases Akt phosphorylation and consecutively reduces phosphorylation of its down-stream targets such as Bad, forkhead transcription factors, and GSK-3 beta [50][51][52][53]. Moreover, neuroprotective agents alleviate MCAO-induced decreases in phosphorylation of Akt and its down-stream targets [50][51][52][53].…”

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“…Akt phosphorylates AS160 causing it to dissociate from the insulin-responsive isoform of the glucose transporter GLUT4 located in intracellular storage vesicles, which facilitates its exocytosis to the plasma membrane. In this regard, Akt removes glucose from circulation and reduces hyperglycemia [129]. Akt also phosphorylates CRTC2, a CREB co-activator, that increases hepatic gluconeogenesis hence controlling the release of de novo glucose into the blood [130].…”

“…In another model, middle cerebral artery occlusion (MCAO), rats who simultaneously received FA did not experience a decrease in the levels of phosphorylated Akt or elevated GSK3β and FA further attenuated the increase in phosphorylated CRMP-2 indicating that FA should indeed elicit an effect on Akt, ultimately affecting the GSK3β/CRMP signaling pathway [129]. In the same model, it was also shown that FA rescued the attenuated levels of mTOR, p70S6K and S6 phorphorylation levels describing its neuroprotective role [191].…”