Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1G93A transgenic mice

Xiaojie Zhang, Sheng Chen, Liang Li, Qian Wang, Weidong Le

Research output: Contribution to journalArticle

59 Scopus citations

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 SOD1G93A 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 SOD1G93A 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-α) 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.

Original languageEnglish (US)
Pages (from-to)1112-1119
Number of pages8
JournalNeuropharmacology
Volume54
Issue number7
DOIs
StatePublished - Jun 2008

Keywords

  • Amyotrophic lateral sclerosis
  • Copper/zinc superoxide dismutase
  • Folic acid
  • Homocysteine
  • Neuroprotection
  • Vitamin B12

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

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