Ferulic Acid Administered at Various Time Points Protects against Cerebral Infarction by Activating p38 MAPK/p90RSK/CREB/Bcl-2 Anti-Apoptotic Signaling in the Subacute Phase of Cerebral Ischemia-Reperfusion Injury in Rats

• Published in: PloS one 2016-05, Vol.11 (5), p.e0155748-e0155748
• Main Authors: Cheng, Chin-Yi, Tang, Nou-Ying, Kao, Shung-Te, Hsieh, Ching-Liang
• Format: Article
• Language: English
• Subjects: Acids; Animals; Apoptosis; Apoptosis - drug effects; BAX protein; Bcl-2 protein; Bcl-x protein; Biology and life sciences; Brain research; Carotid arteries; Caspase; Caspase-3; Cerebral blood flow; Cerebral infarction; Cerebral Infarction - etiology; Cerebral Infarction - prevention & control; Chinese medicine; Cortex; Coumaric Acids - therapeutic use; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cytochrome; Cytochrome c; Dosage and administration; Drug therapy; Ferulic acid; Gamma oryzanol; Gene expression; Genetic aspects; Glial fibrillary acidic protein; Gliosis; Hypoxia; Infarction; Ischemia; Kinases; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Medicine and Health Sciences; Metabolism; Mitochondria; Mitogen-activated protein kinases; Neurological diseases; Neuronal-glial interactions; Neuroprotection; Neuroprotective Agents - therapeutic use; Neurosciences; Occlusion; p38 Mitogen-Activated Protein Kinases - metabolism; Physiological aspects; Protein kinase; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Ribosomal protein S6 kinase; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; Rodents; Signal transduction; Signaling; Stroke; Time Factors; Veins & arteries
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0155748

This study aimed to evaluate the effects of ferulic acid (FA) administered at various time points before or after 30 min of middle cerebral artery occlusion (MCAo) followed by 7 d of reperfusion and to examine the involvement of mitogen-activated protein kinase (MAPK) signaling pathways in the cortical penumbra. FA was intravenously administered to rats at a dose of 100 mg/kg 24 h before ischemia (B-FA), 2 h before ischemia (P-FA), immediately after ischemic insult (I-FA), 2 h after reperfusion (R-FA), or 24 h after reperfusion (D-FA). Our study results indicated that P-FA, I-FA, and R-FA effectively reduced cerebral infarct areas and neurological deficits. P-FA, I-FA, and R-FA significantly downregulated glial fibrillary acidic protein (GFAP), mitochondrial Bax, cytochrome c, and cleaved caspase-3 expression, and effectively restored the phospho-p38 MAPK (p-p38 MAPK)/p38 MAPK ratio, phospho-90 kDa ribosomal S6 kinase (p-p90RSK) expression, phospho-Bad (p-Bad) expression, the phospho-cAMP response element-binding protein (p-CREB)/CREB ratio, the cytosolic and mitochondrial Bcl-2/Bax ratios, and the cytosolic Bcl-xL/Bax ratio in the cortical penumbra 7 d after reperfusion. SB203580, a specific inhibitor of p38 MAPK, administered 30 min prior to ischemia abrogated the downregulating effects of I-FA on cerebral infarction, and mitochondrial Bax and cleaved caspase-3 expression, and the upregulating effects of I-FA on the p-p38 MAPK/p38 MAPK ratio, p-p90RSK expression, p-Bad expression, and the p-CREB/CREB, and cytosolic and mitochondrial Bcl-2/Bax ratios. Our study results thus indicate that P-FA, I-FA, and R-FA effectively suppress reactive astrocytosis and exert neuroprotective effects against cerebral infarction by activating p38 MAPK signaling. The regulating effects of P-FA, I-FA, and R-FA on Bax-induced apoptosis result from activation of the p38 MAPK/p90RSK/CREB/Bcl-2 signaling pathway, and eventually contribute to inhibition of the cytochrome c-mediated caspase-3-dependent apoptotic pathway in the cortical penumbra 7 d after reperfusion.