Valproic acid improves locomotion in vivo after SCI and axonal growth of neurons in vitro

Abstract

Previous studies have found that valproic acid (VPA), a histone deacetylases (HDAC) inhibitor, improves outcomes in a rat model of spinal cord injury (SCI). The study here aimed to further illuminate the neuroprotective effects of VPA against SCI, both in vivo and in vitro. First, spinal cord injury was performed in rats using NYU impactor. Delayed VPA injection (8 h following SCI) significantly accelerated locomotor recovery. VPA therapy also suppressed SCI-induced hypoacetylation of histone and promoted expressions of BDNF and GDNF. Next, the influence of VPA on axonal growth inhibited by a myelin protein was tested. Neurons from embryonic spinal cord or hippocampus were cultured on plates coated with Nogo-A peptide, and escalating concentrations of VPA were added into the cultures. VPA treatment, in a concentration dependent manner, allowed neurons to overcome Nogo-A inhibition of neurite outgrowth. Meanwhile, VPA exposure increased the level of histone acetylation and expression of BDNF in spinal neurons. Cumulatively, these findings indicate that VPA is possibly a promising medication and deserves translational trials for spinal cord injury.

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

“…Anti-inflammation. In a rat pMCAO model, VPA treatment markedly reduced the number of both Ischemic stroke Rat and mouse MCAO models; rat global ischemia model Ren et al, 2004;Kim et al, 2007;Qian et al, 2010;Tsai et al, 2011;Wang et al, 2011aWang et al, , 2012Xuan et LPS-treated midbrain neuron-glia co-cultures; cellular, rat and mouse MPTP models; rotenone-challenged cellular and rat models Peng et al, 2005;Chen et al, 2006Chen et al, , 2007Wu et al, 2008;Castro et al, 2012;Schneider, 2010, 2011;Monti et al, 2010;Xiong et al, 2011 Retinal degeneration Rat retinal ganglion cells; rat retinal ischemia model; optic nerve crush; mice Biermann et al, 2010Biermann et al, , 2011Zhang et al, 2011bZhang et al, , 2012b Spinal cord injury Adult rats and mice; organotypic culture of spinal cord Abematsu et al, 2010;Lv et al, 2011Lv et al, , 2012Penas et al, 2011;Lee et al, 2012b Therapeutic Potential of Mood Stabilizers activated microglia and infiltrating monocytes/macrophages and suppressed ischemia-induced upregulation of proinflammatory factors, inducible nitric oxide synthase, and COX-2 . The antiinflammatory effects of VPA have also been demonstrated in vitro.…”

Transcriptional and Epigenetic Regulation in Injury-Mediated Neuronal Dendritic Plasticity

“…Alternatively, histone deacetylases (HDACs) eliminate these acetyl groups, compress chromatin, and repress transcription. As described in a recent review by Lv et al [61], overall spinal cord levels of acetylation are downregulated in rat models of SCI, and giving valproic acid (VPA), a class I HDAC inhibitor, increases acetylation and enhances the recovery of function [61][62][63]. Whether or not these effects of VPA are the result of the direct influence on chromatin modification is unclear, as VPA modulates various intracellular signaling pathways and has its own neuroprotective effects [64].…”

Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats

“…To minimize the possible adverse effects cause by the inhibitory effect of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI [21,[33][34][35], we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Then, mRNA and protein expression levels of two neuronal markers, DCX and NeuN, in epicenter, adjacent segment and distant segment were analyzed (Fig.…”