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Title of Journal: Mol Neurobiol

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Abbravation: Molecular Neurobiology

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Springer US

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DOI

10.1016/0042-207x(68)92197-0

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ISSN

1559-1182

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Role of Rho Kinase Inhibition in the Protective Ef

Authors: Lamiaa A Ahmed Hebatallah A Darwish Rania M Abdelsalam HebatAllah A Amin
Publish Date: 2015/07/15
Volume: 53, Issue: 6, Pages: 3927-3938
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Abstract

3Nitropropionic acid 3NPinduced neurotoxicity is an experimental model which mimics the pathology and motor abnormalities seen in Huntington’s disease HD in human The present investigation was directed to estimate the role of rho kinase ROCK inhibition in the possible protective effect of fasudil and simvastatin in 3NPinduced striatal neurodegeneration in rats Animals were injected sc with 3NP 20 mg/kg/day for 1 week with or without administration of fasudil 10 mg/kg/day po or simvastatin 20 mg/kg/day po At the end of experiment motor and behavioral abnormalities were evaluated Animals were then sacrificed for measurement of mitochondrial membrane potential as well as succinate dehydrogenase SDH and caspase3 activities in striatum Moreover tumor necrosis factoralpha TNFα level and protein expressions of proliferatoractivated receptor gamma coactivator 1alpha PGC1α ROCK phosphorylatedAkt pAkt endothelial and inducible nitric oxide synthase eNOS and iNOS Bax and Bcl2 were estimated Finally histological changes as demonstrated by striatum injury score glial activation and percentage of altered mitochondria were assessed Both fasudil and simvastatin effectively inhibited 3NPinduced behavioral biochemical and histological changes through inhibition of ROCK activity However fasudil provided more amelioration in histological changes mitochondrial membrane potential and SDH activity in addition to pAkt and PGC1α protein expressions The present study highlights a significant role of ROCK/pAkt/eNOS pathway in the protective effects of fasudil and simvastatin on neurotoxicity and mitochondrial dysfunction induced by 3NP in rats Thus specific inhibition of ROCK may be considered a promising new approach in the management of HD

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