title: Inhibition of sonic hedgehog signaling aggravates brain damage associated with the down-regulation of Gli1, Ptch1 and SOD1 expression in acute ischemic stroke.
abstract: Oxidative and cytotoxic damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Recent studies have indicated that sonic hedgehog (Shh) signaling could protect neurons against oxidative stress by increasing superoxide dismutase 1 (SOD1) activity. Glioma-associated oncogene homolog 1 (Gli1) and patched-1 (Ptch1) are both components and transcriptional targets of the Shh pathway. Here, we designed this study to determine the effect of inhibition of Shh pathway on the development of cerebral ischemia injury. Male, Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (pMCAO). Cyclopamine (0.18mg/kg), the classical inhibitor of Shh signaling, was stereotactic injected into the lateral cerebral ventricle immediately after pMCAO. At 24h neurological deficit was evaluated using a modified six point scale; brain water content was measured; infarct size was analyzed with 2,3,5-triphenyltetrazolium chloride (TTC). Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), Western Blotting and activity assay were used to analyze the expression of Gli1, Ptch1 and SOD1. Compared with Vehicle group, cyclopamine down-regulated Gli1, Ptch1 and SOD1 in pMCAO-affected brain tissue (P<0.05), and increased infarct volume (P<0.05), brain water content (P<0.05) and behavioral deficits (P<0.05). Collectively, the present results suggest that inhibition of Shh signaling pathway exacerbated rat ischemic damage caused by pMCAO, which may be correlated with down-regulated expression of Gli1, Ptch1 and SOD1.
authors: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, PR China.
authors: Hui
authors: H
authors: Ji
authors: Jiangyong
authors: J
authors: Miao
authors: Xiangjian
authors: X
authors: Zhang
authors: Yuanyuan
authors: Y
authors: Du
authors: Haichao
authors: H
authors: Liu
authors: Shuya
authors: S
authors: Li
authors: Litao
authors: L
authors: Li
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001929:Brain Edema / Q000209:etiology; D020520:Brain Infarction / Q000209:etiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009460:Neurologic Examination; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013778:Tetrazolium Salts; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: C498521:Gli1 protein, rat; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606239:Ptch1 protein, rat; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C546888:Shh protein, rat; D013778:Tetrazolium Salts; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C009591:triphenyltetrazolium; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000541:cyclopamine