Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3

Abstract

BackgroundMicroglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear factor-κB (NF-κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential molecular mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment.MethodsThe Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to determine the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot analysis were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI.ResultsThe results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI.ConclusionsThese results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI.

Application of stem cells and chitosan in the repair of spinal cord injury

“…Diverse neurotrophic factors have contributed to the poor axonal regrowth and ineffective functional recovery in the SCI repair process (Chen et al, 2018a,2018b; Mesentier‐Louro et al, 2019). It has been reported that glial cell line‐derived neurotrophic factor (GDNF) has protective potential in neurodegeneration disease(Mukhamedshina et al, 2016).…”

“…However, the existing treatment strategies have not exhibited significant potential to cure SCI. The pathophysiologic mechanism of SCI is complicated and includes the loss of neurons and glial cells, degeneration of extracellular matrix architecture and destruction of the neural circuit at the lesion site (Kumar et al, 2015; Chen et al, 2018a). Current strategies to cure SCI include surgical decompression (Jug et al, 2015; Liu et al, 2016) and pharmacotherapy (Wang et al, 2019) as well as focus on the restoration of nerve function by enhancing the survival of neurons after injury and promotion of axon regeneration via the injury site.…”

VPA/PLGA microfibers produced by coaxial electrospinning for the treatment of central nervous system injury

“…Previous studies have demonstrated that systemic administration of valproic acid (VPA) improved locomotor function after SCI (6)(7)(8). In addition, VPA exerts an anti-inflammatory effect (9), reduces cell death of motor neurons (10) and cellular apoptosis (11), attenuates demyelination and axonal loss, preserves the oligodendrocytes and neurons (6), increases neurite outgrowth (12), reduces the cystic cavity (8), and increases expression of neuronal progenitor cells in the spinal cord (13).…”

Methods of An Open-Label Proof-Of-Concept Trial of Intravenous Valproic Acid for Severe COVID-19

“…12 This molecule has also shown intrinsic antiviral activity probably due to its activity as histone deacetylase inhibitor. 9,[13][14][15][16] VPA has shown anti-inflammatory activity in myocardial 17 as well as neural tissue in models of brain and spinal cord injuries, 18,19 although with some conflicting findings. 20 Although long-term adverse effects and even pro-inflammatory consequences have been reported with the chronic use of VPA, 12 we believe that, given the urgent need to have .…”