title: 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.
abstract: OBJECTIVE
  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.
  
  
  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 24h.
  
  
  RESULTS
  WA treatment (25, 50 or 100mg/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.
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China; Department of Neurology, The Fifth People's Hospital of Jinan, Jinan 250022, Shandong, China.
authors.forename: Qi-Zhi
authors.initials: QZ
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Fifth People's Hospital of Jinan, Jinan 250022, Shandong, China.
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Guo
authors.affiliation: Department of Internal Medicine, Jinan Institute of Dermatology, Jinan 250001, Shandong, China.
authors.forename: Hao-Mei
authors.initials: HM
authors.lastname: Li
authors.affiliation: Department of Science Education, The Fifth People's Hospital of Jinan, Jinan 250022, Shandong, China.
authors.forename: Rui-Zheng
authors.initials: RZ
authors.lastname: Wang
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China.
authors.forename: Shou-Gang
authors.initials: SG
authors.lastname: Guo
authors.affiliation: Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China. Electronic address: duyifengf@hotmail.com.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D054358:Withanolides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020782:Matrix Metalloproteinases; C009684:withaferin A
keywords: Apoptosis cerebral infarction; Matrix metalloproteinases; PI3K/Akt signaling pathway; Vascular smooth muscle cells; Withaferin A