Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice

Neuropharmacology. 2008 Jun;54(7):1112-9. doi: 10.1016/j.neuropharm.2008.02.020. Epub 2008 Mar 16.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by selective degeneration of motor neurons. Mutations in copper/zinc superoxide dismutase (SOD1) account for 20% cases of familial ALS (fALS), but the underlying pathogenetic mechanisms are largely unknown. Using SOD1(G93A) mice model of ALS, we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine (Hcy). To investigate whether Hcy-lowering therapy is beneficial to this disease, we applied folic acid (FA) and vitamin B12 which are important factors involved in the Hcy metabolism to assess the neuroprotective effect of FA and B12 in the SOD1(G93A) mice. Our results showed FA or FA+B12 treatment significantly delayed the disease onset and prolonged the lifespan, accompanied by the significant reduction of motor neuron loss. Furthermore, we found that FA or FA+B12 treatment significantly attenuated the plasma Hcy level, suppressed the activation of microglia and astrocytes, and inhibited the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord. Moreover, FA or FA+B12 treatment decreased the levels of cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) but up-regulated the level of anti-apoptotic protein Bcl-2. However, B12 treatment alone did not show any significant benefit to this disease. These results provide evidence to demonstrate that elevated Hcy is involved in the pathogenesis of fALS and FA therapy may have therapeutic potential for the treatment of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / blood
  • Amyotrophic Lateral Sclerosis* / drug therapy
  • Amyotrophic Lateral Sclerosis* / pathology
  • Animals
  • Apoptosis / drug effects*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay / methods
  • Folic Acid / therapeutic use*
  • Gas Chromatography-Mass Spectrometry / methods
  • Homocysteine / blood*
  • Inflammation / drug therapy*
  • Inflammation / etiology
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects*
  • Nitric Oxide Synthase Type II / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Random Allocation
  • Rotarod Performance Test / methods
  • Spinal Cord / pathology
  • Superoxide Dismutase / genetics
  • Vitamin B 12 / therapeutic use
  • Vitamin B Complex / therapeutic use*

Substances

  • Cytokines
  • Proto-Oncogene Proteins c-bcl-2
  • Homocysteine
  • Vitamin B Complex
  • Folic Acid
  • Nitric Oxide Synthase Type II
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Vitamin B 12