Spinal cord injury (SCI) is a serious disease of the central nervous system that involves the loss of sensorimotor function at and below the spinal level of injury.1,2 SCI can be divided into primary SCI and secondary SCI. Primary SCI usually results from acute spinal cord compression and rapid neuronal cell death caused by direct trauma (such as a vehicle accident, fall, violence, or contusion and compression during sports) and pathological changes (such as cancer).1, 2, 3 The pathophysiological cascade caused by primary SCI develops into secondary SCI, which is more complex than primary SCI.2 The initiation of secondary injury results in increased proinflammatory cytokines, proteoglycan deposition, and glutamate excitotoxicity, overall exacerbating cell death, and preventing neural regeneration.2,4 In addition to the loss of motor and sensory function, patients with SCI experience a range of serious consequences, such as neuropathic pain, pressure sores, psychological disorders, and bladder and rectal dysfunction.5,6 SCI causes great physical and psychological suffering to patients, and a huge economic burden globally.7,8 At present, decompression surgery, glucocorticoids (methylprednisolone), anti-inflammatory drugs (ketorolac, minocycline), and analgesics are the main clinical methods for the treatment of patients with SCI.6,9 However, these treatments have not achieved satisfactory results. In addition, these drugs have many adverse reactions, such as suppression of autoimmunity, liver and kidney damage, and drug dependence.6 Therefore, the treatment of patients with SCI remains a major challenge for the medical community.

In recent years, with the development of science and technology, the pathogenesis of SCI continues to be elucidated. Valproic acid (VPA) may be 1 of the effective means to treat SCI. VPA is a potent inhibitor of histone deacetylases (HDACs),10 which plays an important role in the inflammatory response and repair process of cells and tissues.11 HDACs are involved in regulating the expression of inflammatory genes and interact with a variety of transcription factors such as nuclear factor kappa-κB (NF-κB), thereby inhibiting the transcription of inflammatory genes and reducing the expression of inflammatory proteins.12 At the same time, VPA mediates acetylation of STAT1 involved in NF-κB, and inhibition of HDAC3, resulting in the activation of microglia towards the M2 (anti-inflammatory) phenotype, reducing expression of pro-inflammatory cytokines, thereby inhibiting the inflammatory response of SCI.13 It is worth noting that relevant in vitro and in vivo studies have shown that VPA has anti-inflammatory and neuroprotective effects, which can significantly promote functional recovery in rats with SCI.14,15 Currently, VPA is widely used to treat neurological and psychiatric disorders, including seizures, neuropathic pain, and bipolar mood disorders.16 VPA has excellent neuroprotective effects on a variety of neurological diseases, including spinal muscular atrophy, amyotrophic lateral sclerosis, transient or permanent middle cerebral artery occlusion, cerebral hemorrhage, traumatic brain injury, and experimental autoimmune neuritis.17 It has been reported that VPA significantly enhanced the recovery of hind limb function in mice with SCI by promoting the differentiation of neural stem cells into neuronal cells.18 It has been reported that the accumulation of microglia, macrophages, and astrocytes at the injury epicenter was significantly reduced in VPA-injected rats with SCI.19 In addition, many studies have shown that VPA can promote axon regeneration and functional recovery in rats with SCI.19,20 VPA has been demonstrated to be neuroprotective, while also contributing to reduced inflammation in different neurological diseases.

VPA has good anti-inflammatory effects, antioxidative stress, and the ability to promote tissue repair.21,22 VPA also can promote neuronal regeneration and recovery of motor function. At the same time, the pathophysiology of rats with SCI is similar to that of humans with SCI. However, VPA has not been used to treat SCI, and a comprehensive review of its benefit towards functional recovery in SCI has yet to be examined. Therefore, we evaluated the actual efficacy of VPA in restoring motor function in rats with SCI through a systematic review and meta-analysis, with the expectation of reducing the risk of clinical translation and providing a valuable reference for future animal and clinical studies.