title: Preferential PPAR-α activation reduces neuroinflammation, and blocks neurodegeneration in vivo.
abstract: Neuroinflammation, immune reactivity and mitochondrial abnormalities are considered as causes and/or contributors to neuronal degeneration. Peroxisome proliferator-activated receptors (PPARs) regulate both inflammatory and multiple other pathways that are implicated in neurodegeneration. In the present study, we investigated the efficacy of fenofibrate (Tricor), a pan-PPAR agonist that activates PPAR-α as well as other PPARs. We administered fenofibrate to superoxide dismutase 1 (SOD1(G93A)) mice daily prior to any detectable phenotypes and then animal behavior, pathology and longevity were assessed. Treated animals showed a significant slowing of the progression of disease with weight loss attenuation, enhanced motor performance, delayed onset and survival extension. Histopathological analysis of the spinal cords showed that neuronal loss was significantly attenuated in fenofibrate-treated mice. Mitochondria were preserved as indicated by Cytochrome c immunostaining in the spinal cord, which maybe partly due to increased expression of the PPAR-γ co-activator 1-α. The total mRNA analysis revealed that neuroprotective and anti-inflammatory genes were elevated, while neuroinflammatory genes were down-regulated. This study demonstrates that the activation of PPAR-α action via fenofibrate leads to neuroprotection by both reducing neuroinflammation and protecting mitochondria, which leads to a significant increase in survival in SOD1(G93A) mice. Therefore, the development of therapeutic strategies to activate PPAR-α as well as other PPARs may lead to new therapeutic agents to slow or halt the progression of amyotrophic lateral sclerosis.
authors.affiliation: Department of Neurobiology and Developmental Sciences, Center for Translational Neuroscience and.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Esmaeili
authors.affiliation: Department of Neurobiology and Developmental Sciences, Center for Translational Neuroscience and.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, 72205 AR, USA and.
authors.forename: Ravi Kr
authors.initials: RK
authors.lastname: Gupta
authors.affiliation: Department of Neurobiology and Developmental Sciences, Center for Translational Neuroscience and.
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Waggoner
authors.affiliation: Department of Neurobiology and Developmental Sciences, Center for Translational Neuroscience and.
authors.forename: Abigail
authors.initials: A
authors.lastname: Deloach
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.affiliation: Department of Neurobiology and Developmental Sciences, Center for Translational Neuroscience and, mkiaei@uams.edu kiaeim@yahoo.com.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D011345:Fenofibrate / Q000276:immunology / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000276:immunology / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology
chemical_list: D018696:Neuroprotective Agents; D047493:PPAR alpha; D011345:Fenofibrate