Spinal inflammation is a pathophysiological state of neuropathic pain (NP). The subsequent microglial activation and neuroinflammatory response are contributing factors for long-lasting behavioral hypersensitivity. Valproic acid (VPA), a histone deacetylase inhibitor, has promising anti-inflammatory and neuroprotective properties for clinical use in the treatment of neurological disorders. However, the underlying mechanisms of its effects on NP have not been determined. This study aimed to clarify the possible mechanisms by which VPA alleviates NP in rat models induced by spinal nerve ligation (SNL).

Intraperitoneal injection of VPA (300 mg/kg) efficiently attenuated mechanical allodynia in rats with NP. VPA exerted anti-inflammatory effects by downregulating proinflammatory cytokines (tumor necrosis factor-α, cytokines interleukin-1β, cytokines interleukin-6; TNF-α, IL-1β, and IL-6) and upregulating anti-inflammatory cytokines (transforming growth factor-β, cytokines interleukin-10, cytokines interleukin-4; TGF-β, IL-10 and IL-4). Additionally, VPA suppressed spinal microgliosis and promoted the polarization of microglia towards the M2 phenotype to further ameliorate spinal neuroinflammation. VPA also exerted neuroprotective effects by decreasing spinal cell apoptosis. The anti-inflammatory and neuroprotective effects may have depended on changes in nuclear histone deacetylase 3 (HDAC3) expression following VPA treatment. Moreover, VPA treatment inhibited nuclear factor-κB (NF-κB) p65 nuclear expression and upregulated acetylated the signal transducer and activator of transcription 1 (STAT1). In addition, VPA suppressed SNL-induced phosphorylation of Janus Kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Taken together, our results demonstrate that VPA is a promising anti-inflammatory agent suitable for NP therapy that regulates microglial function and suppresses spinal neuroinflammation via the STAT1/NF-κB and JAK2/STAT3 signaling pathways.

脊柱炎症是神经性疼痛（NP）的病理生理状态。随后的小胶质细胞激活和神经炎性反应是长期行为超敏反应的促成因素。组蛋白脱乙酰基酶抑制剂丙戊酸（VPA）具有有希望的抗炎和神经保护特性，可用于临床治疗神经系统疾病。然而，尚未确定其对NP的影响的潜在机制。本研究旨在阐明VPA缓解脊髓神经结扎（SNL）诱导的大鼠模型中NP的可能机制。

腹膜内注射VPA（300 mg / kg）可有效减轻NP大鼠的机械性异常性疼痛。VPA通过下调促炎细胞因子（肿瘤坏死因子-α，白细胞介素-1β，白细胞介素-6；TNF-α，IL-1β和IL-6）和上调抗炎细胞因子（转化生长因子）发挥抗炎作用。 -β，白细胞介素10，白细胞介素4；TGF-β，IL-10和IL-4。此外，VPA抑制了脊髓小胶质细胞增生，并促进了小胶质细胞向M2表型的极化，从而进一步减轻了脊柱神经炎症。VPA还通过减少脊髓细胞凋亡发挥神经保护作用。抗炎和神经保护作用可能取决于VPA治疗后核组蛋白脱乙酰基酶3（HDAC3）表达的变化。此外，VPA处理可抑制核因子-κB（NF-κB）p65核表达，并上调乙酰化信号转导子和转录激活子1（STAT1）。此外，VPA抑制了SNL诱导的Janus激酶2（JAK2）和信号转导和转录激活因子3（STAT3）的磷酸化。综上所述，我们的结果表明，VPA是一种有前途的抗炎药，适用于NP治疗，可通过STAT1 /NF-κB和JAK2 / STAT3信号通路调节小胶质细胞功能并抑制脊髓神经炎症。