期刊
NEUROCHEMISTRY INTERNATIONAL
卷 61, 期 8, 页码 1357-1363出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2012.09.013
关键词
Lanthionines; Stroke; CRMP2; PARP-1; Ischemia; SIRT-1
资金
- National Institutes of Health [R00-AT004197, R01-AE031553, R21-NS066279]
Lanthionines are novel neurotrophic and neuroprotective small molecules that show promise for the treatment of neurodegenerative diseases. In particular, a recently developed, cell permeable lanthionine derivative known as LICE (lanthionine ketimine 5-ethyl ester) promotes neurite growth at low nanomolar concentrations. LKE also has neuroprotective, anti-apoptotic, and anti-inflammatory properties. Its therapeutic potential in cerebral ischemia and its mechanisms of neurotrophic action remain to be fully elucidated. Here, we hypothesize that the neuroprotective actions of LICE could result from induction or modulation of CRMP2. We found that treating primary cultured mouse neurons with LKE provided significant protection against t-butyl hydroperoxide-induced neuronal death possibly through CRMP2 upregulation. Similarly, in vivo studies showed that LICE pre and/or post-treatment protects mice against permanent distal middle cerebral artery occlusion (p-MCAO) as evidenced by lower stroke lesions and improved functional outcomes in terms of rotarod, grip strength and neurologic deficit scores in treated groups. Protein expression levels of CRMP2 were higher in brain cortices of LICE pretreated mice, suggesting that LKE's neuroprotective activity may be CRMP2 dependent. Lower activity of cleaved PARP-1 and higher activity of SIRT-1 was also observed in LICE treated group suggesting its anti-apoptotic properties. Our results suggest that LICE has potential as a therapeutic intervention in cerebral ischemia and that part of its protective mechanism may be attributed to CRMP2 mediated action and PARP-1/SIRT-1 modulation. (C) 2012 Elsevier Ltd. All rights reserved.
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