Effects of valproic acid, a histone deacetylase inhibitor, on improvement of locomotor function in rat spinal cord injury based on epigenetic science

ABSTRACT

The primary phase of traumatic spinal cord injury [SCI] starts by a complex local inflammatory reaction such as secretion of pro-inflammatory cytokines from microglia and injured cells that substantially contribute to exacerbating pathogenic events in secondary phase. Valproic acid [VPA] is a histone deacetylase inhibitor. Acetylation of histones is critical to cellular inflammatory and repair processes. In this study, rats were randomly assigned to five experimental groups [laminectomy, untreated, and three VPA-treated groups]. For SCI, severe contusion was used. In treated groups, VPA was administered intraperitoneally at doses of 100, 200 and 400 mg/kg daily three hours after injury for 7 days. To compare locomotor improvement among experimental groups, behavioral assessments were performed by the Basso, Beattie and Bresnahan [BBB] rating scale. The expression of neurotrophins was evaluated by RT-PCR and real-time PCR. VPA administration increased regional brain-derived neurotrophic factor and glial cell-derived neurotrophic factor mRNA levels. Local inflammation and the expression of the lysosomal marker ED1 by activated macrophages/microglial cells were reduced by VPA and immunoreactivity of acetylated histone and microtubule-associated protein were increased. The results showed a reduction in the development of secondary damage in rat spinal cord trauma with an improvement in the open field test [BBB scale] with rapid recovery