Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel (2 mg/kg, i.p., cumulative dose 8 mg/kg) induced long-lasting mechanical allodynia (>28 days) with increased glutamate concentration and decreased EAAT2 expression with no changes in GABA/glycine or VGAT (vesicular GABA transporter) in rat spinal dorsal horn. VGLUT2 expression was upregulated and coexpressed with enhanced synaptophysin, characterizing nociceptive afferent sprouting and new synapse formation of glutamatergic neurons in the spinal cord dorsal horn. HDAC2 and transcription factor YY1 were also upregulated, and their interaction and colocalization were confirmed following paclitaxel treatment using co-immunoprecipitation. Inhibition or knockdown of HDAC2 expression by valproic acid, BRD6688, or HDAC2 siRNA not only attenuated paclitaxel-induced mechanical allodynia but also suppressed HDAC2 upregulation, glutamate accumulation, and the corresponding changes in EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction. These findings indicate that loss of the balance between glutamate release and reuptake due to dysregulation EAAT2/VGLUT2/synaptophysin cascade in the spinal dorsal horn plays an important role in the development of paclitaxel-induced neuropathic pain. HDAC2/YY1 interaction as a complex appears essential in regulating this pathway, which can potentially be a therapeutic target to relieve CIPN by reversing central sensitization of spinal nociceptive neurons.

中文翻译：

---

EAAT2 和 VGLUT2 通过组蛋白去乙酰化酶 2 (HDAC2) 的脊髓谷氨酸转运失调导致紫杉醇诱导的疼痛性神经病变

化疗引起的周围神经病变 (CIPN) 的有效治疗方法仍然不可用。鉴于脊髓谷氨酸转运蛋白在神经元可塑性和中枢敏化中的重要性，本研究调查了兴奋性氨基酸转运蛋白 2 (EAAT2) 和囊泡谷氨酸转运蛋白 2 (VGLUT2) 在紫杉醇诱发的疼痛性神经病变发展中的作用。紫杉醇（2 毫克/千克，腹腔注射，累积剂量 8 毫克/千克）诱导长期机械性异常性疼痛（>28 天），谷氨酸浓度增加，EAAT2 表达降低，而 GABA/甘氨酸或 VGAT（囊泡 GABA 转运蛋白）没有变化大鼠脊髓背角。VGLUT2 表达上调并与增强的突触素共表达，表征脊髓背角谷氨酸能神经元的伤害性传入发芽和新突触形成。HDAC2 和转录因子 YY1 也被上调，并且在紫杉醇处理后使用共免疫沉淀证实了它们的相互作用和共定位。通过丙戊酸、BRD6688 或 HDAC2 siRNA 抑制或敲低 HDAC2 表达不仅可以减轻紫杉醇引起的机械性异常性疼痛，还可以抑制 HDAC2 上调、谷氨酸积累以及 EAAT2/VGLUT/突触素表达和 HDAC2/YY1 相互作用的相应变化。这些发现表明，由于脊髓背角中 EAAT2/VGLUT2/突触素级联失调导致的谷氨酸释放和再摄取之间平衡的丧失在紫杉醇诱导的神经性疼痛的发展中起着重要作用。HDAC2/YY1 相互作用作为一种复合物似乎在调节该通路中必不可少，这可能是通过逆转脊髓伤害性神经元的中枢敏化来缓解 CIPN 的治疗靶点。