title: SIRT1 activating compounds reduce oxidative stress mediated neuronal loss in viral induced CNS demyelinating disease.
abstract: BACKGROUND
  Multiple sclerosis (MS) is characterized by central nervous system inflammation and demyelination, and increasing evidence demonstrates significant neuronal damage also occurs and is associated with permanent functional impairment. Current MS therapies have limited ability to prevent neuronal damage, suggesting additional neuroprotective therapies are needed. Compounds that activate the NAD+-dependent SIRT1 deacetylase prevent neuronal loss in an autoimmune-mediated MS model, but the mechanism of this effect is unknown, and it is unclear whether SIRT1 activating compounds exert similar effects in demyelinating disease induced by other etiologies. We measured neuronal loss in C57BL/6 mice inoculated with a neurotropic strain of mouse hepatitis virus, MHV-A59, that induces an MS-like disease.
  
  
  RESULTS
  Oral treatment with the SIRT1 activating compound SRTAW04 significantly increased SIRT1 activity within optic nerves and prevented neuronal loss during optic neuritis, an inflammatory demyelinating optic nerve lesion that occurs in MS and its animal models. MHV-A59 induced neuronal loss was associated with reactive oxygen species (ROS) accumulation, and SRTAW04 treatment significantly reduced ROS levels while promoting increased expression of enzymes involved in mitochondrial function and reduction of ROS. SRTAW04 exerted similar protective effects in EAE spinal cords, with decreased demyelination.
  
  
  CONCLUSIONS
  Results demonstrate that SIRT1 activating compounds prevent neuronal loss in viral-induced demyelinating disease similar to their effects in autoimmune-mediated disease. One mechanism of this neuroprotective effect involves increasing mitochondrial biogenesis with reduction of oxidative stress. SIRT1 activators represent a potential neuroprotective therapy for MS. Understanding common mechanisms of these effects in distinct disease models will help identify targets for more specific therapies.
authors.forename: Reas S
authors.initials: RS
authors.lastname: Khan
authors.forename: Kimberly
authors.initials: K
authors.lastname: Dine
authors.affiliation: Department of Ophthalmology, Scheie Eye Institute and FM Kirby Center for Molecular Ophthalmology, Stellar-Chance Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA. dassarmaj@iiserkol.ac.in.
authors.forename: Jayasri
authors.initials: J
authors.lastname: Das Sarma
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Shindler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use; D020278:Demyelinating Autoimmune Diseases, CNS / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology* / Q000821:virology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006518:Hepatitis Viruses / Q000472:pathogenicity; D006524:Hepatitis, Viral, Animal / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013266:Stilbamidines; D013997:Time Factors
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D013266:Stilbamidines; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1