Protection against cerebral infarction by Withaferin A involves inhibition of neuronal apoptosis, activation of PI3K/Akt signaling pathway, and reduced intimal hyperplasia via inhibition of VSMC migration and matrix metalloproteinases
| Autor: | Hao-Mei Li, Shou-Gang Guo, Yi-Feng Du, Rui-Zheng Wang, Qi-Zhi Zhang, Yu-Dong Guo |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Intimal hyperplasia Apoptosis mTORC1 Pharmacology Neuroprotection Muscle Smooth Vascular Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Phosphatidylinositol 3-Kinases 0302 clinical medicine Cell Movement medicine Animals Phosphorylation Protein kinase B Withanolides PI3K/AKT/mTOR pathway Cells Cultured Neurons Hyperplasia business.industry General Medicine Cerebral Infarction medicine.disease Matrix Metalloproteinases Rats 030104 developmental biology Neuroprotective Agents chemistry Withaferin A Reperfusion Injury Immunology business Reperfusion injury Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Advances in medical sciences. 62(1) |
| ISSN: | 1898-4002 |
| Popis: | Purpose Stroke is a major public health concern with high rates of morbidity and mortality worldwide. Cerebral ischemia and infarction are commonly associated with stroke. Currently used medications, though effective, are also associated with adverse effects. Development of effective neuroprotective agents with fewer side effects would be of clinical value. We evaluated the effects of Withaferin A (WA), a steroidal lactone derived from the plant Withania somnifera, on experimentally induced cerebral infarction. Materials and methods The ability of WA to inhibit neuroapoptosis and modulate vascular smooth muscle cell (VSMC) migration and PI3K/Akt signaling was assessed. Separate groups of Sprague Dawley rats were subjected to cerebral occlusion and reperfused for 24 h. Results WA treatment (25, 50 or 100 mg/kg bodyweight) significantly reduced the infarct area in a carotid ligation model; WA reduced intimal hyperplasia and proliferating cell nuclear antigen (PCNA)-positive cell counts. Western blotting analysis revealed significantly suppressed PI3K/Akt signaling following cerebral ischemia/reperfusion injury. WA supplementation was found to downregulate apoptotic pathway proteins. WA suppressed PTEN and enhanced p-Akt and GSK-3β levels and elevated mTORc1, cyclinD1 and NF-κB p65 expression, suggesting activation of the PI3K/Akt pathway. In vitro studies with PDGF-stimulated A7r5 cells revealed that WA exposure severely downregulated matrix metalloproteinases (MMP)-2 and -9 and inhibited migration of A7r5 cells. Additionally, WA reduced the proliferation of A7r5 cells significantly. Conclusions WA exerted neuroprotective effects by activating the PI3K/Akt pathway, modulating the expression of MMPs, and inhibiting the migration of VSMCs. |
| Databáze: | OpenAIRE |
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