title: Role of Rho Kinase Inhibition in the Protective Effect of Fasudil and Simvastatin Against 3-Nitropropionic Acid-Induced Striatal Neurodegeneration and Mitochondrial Dysfunction in Rats.
abstract: 3-Nitropropionic acid (3-NP)-induced 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 3-NP-induced striatal neurodegeneration in rats. Animals were injected s.c. with 3-NP (20 mg/kg/day) for 1 week with or without administration of fasudil (10 mg/kg/day, p.o.) or simvastatin (20 mg/kg/day, p.o.). 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 caspase-3 activities in striatum. Moreover, tumor necrosis factor-alpha (TNF-α) level and protein expressions of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ROCK, phosphorylated-Akt (p-Akt), endothelial and inducible nitric oxide synthase (eNOS and iNOS), Bax, and Bcl-2 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 3-NP-induced 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 p-Akt and PGC-1α protein expressions. The present study highlights a significant role of ROCK/p-Akt/eNOS pathway in the protective effects of fasudil and simvastatin on neurotoxicity and mitochondrial dysfunction induced by 3-NP in rats. Thus, specific inhibition of ROCK may be considered a promising new approach in the management of HD.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. lamiaa.ahmed@pharma.cu.edu.eg.
authors.forename: Lamiaa A
authors.initials: LA
authors.lastname: Ahmed
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Hebatallah A
authors.initials: HA
authors.lastname: Darwish
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Rania M
authors.initials: RM
authors.lastname: Abdelsalam
authors.affiliation: Department of Pathology, Forensic Medicine Authority, Ministry of Justice, Cairo, Egypt.
authors.forename: HebatAllah A
authors.initials: HA
authors.lastname: Amin
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009574:Nitro Compounds; D009929:Organ Size / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D009574:Nitro Compounds; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D011422:Propionates; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019821:Simvastatin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013385:Succinate Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D053148:Caspase 3; C049347:fasudil; C015392:3-nitropropionic acid
keywords: Fasudil; Mitochondria; Nitropropionic acid; Simvastatin; Striatum