Valproic acid ameliorates inflammation in experimental autoimmune encephalomyelitis rats

Neuroscience. 2012 Sep 27;221:140-50. doi: 10.1016/j.neuroscience.2012.07.013. Epub 2012 Jul 16.

Abstract

Valproic acid (VPA) is a short-chain branched fatty acid with anti-inflammatory, neuro-protective and axon remodeling effects. Here we have studied effects of VPA in gpMBP(68-84)-induced experimental autoimmune encephalomyelitis (EAE). Both preventive (from Day 0 to Day 18) and therapeutic (from Day 7 to Day 18 or from Day 9 to Day 19) VPA (500 mg/kg, intra-gastric) administration to EAE rats once daily greatly reduced the severity and duration of EAE, and suppressed mRNA levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-17, matrix metalloproteinase 9 (MMP9), inducible nitric oxide synthase (iNOS) and transcription factor T-bet, but increased levels of IL-4 mRNA in EAE spinal cords. Furthermore, preventive VPA treatment greatly attenuated accumulation of macrophages and lymphocytes in EAE spinal cords. VPA treatment altered the cytokine milieu of lymph nodes, modulating the Th profile from Th1 and Th17 to a profile of Th2 and regulatory T cells. In addition, in vitro study showed that VPA inhibited non-specific lymphocyte proliferation in a dose-dependent manner. In summary, our data demonstrated that VPA could suppress systemic and local inflammation to improve outcome of EAE, suggesting that VPA might be a candidate for treatment of multiple sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • CD11b Antigen / metabolism
  • CD3 Complex / metabolism
  • Cell Proliferation / drug effects
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Ectodysplasins / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / complications*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Expression Regulation / drug effects*
  • Inflammation / drug therapy*
  • Lymphocyte Activation / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred Lew
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / metabolism
  • Time Factors
  • Valproic Acid / therapeutic use*

Substances

  • Anti-Inflammatory Agents
  • CD11b Antigen
  • CD3 Complex
  • Cytokines
  • Ectodysplasins
  • Eda protein, mouse
  • RNA, Messenger
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Valproic Acid
  • Nitric Oxide Synthase Type II
  • Matrix Metalloproteinase 9