We previously reported that melatonin protects neuronal cells against ischemic brain damage. In this study, we identified proteins that were differentially expressed by melatonin treatment during ischemic brain injury. Rats were subjected to cerebral ischemia by middle cerebral artery occlusion (MCAO). Adult male rats were treated with melatonin (5 mg/kg) or vehicle prior to MCAO and brains were collected at 24 hr after MCAO. Proteins derived from the cerebral cortex were analyzed using two-dimensional gel electrophoresis. Protein spots with a greater than 2.5-fold change in intensity were identified by mass spectrometry. Among these proteins, gamma-enolase, stathmin, thioredoxin, peroxiredoxin-6, hippocalcin, protein phosphatase 2A, adenosylhomocysteinase, ubiquitin carboxy-terminal hydrolase L1, and NAD-specific isocitrate dehydrogenase subunit alpha were significantly decreased in the vehicle-treated group in comparison to the melatonin-treated group. The identified proteins consist of cell differentiation and stabilization proteins, as well as an antioxidant enzyme. In contrast, dehydroprimidinase-related protein 2 (DRP-2), a target of protein oxidation in neurodegeneration, was significantly increased in vehicle-treated animals, while melatonin prevented the injury-induced increase of DRP-2. Thus, the results of this study suggest that melatonin prevents cell death resulting from ischemic brain injury and that its neuroprotective effects are mediated by both the up- and down-regulation of various proteins.
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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