Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Int J Mol Sci. 2022 Sep 1;23(17):9983. doi: 10.3390/ijms23179983.
Oxaliplatin (OHP) is a platinum-based agent that can cause peripheral neuropathy, an adverse effect in which the dorsal root ganglion (DRG) neurons are targeted. Zonisamide has exhibited neuroprotective activities toward adult rat DRG neurons in vitro and therefore, we aimed to assess its potential efficacy against OHP-induced neurotoxicity. Pretreatment with zonisamide (100 μM) alleviated the DRG neuronal death caused by OHP (75 μM) and the protective effects were attenuated by a co-incubation with 25 μM of the mitogen-activated protein kinase (MAPK; MEK/ERK) inhibitor, U0126, or the phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor, LY294002. Pretreatment with zonisamide also suppressed the OHP-induced p38 MAPK phosphorylation in lined DRG neurons, ND7/23, while the OHP-induced DRG neuronal death was alleviated by pretreatment with the p38 MAPK inhibitor, SB239063 (25 μM). Although zonisamide failed to protect the immortalized rat Schwann cells IFRS1 from OHP-induced cell death, it prevented neurite degeneration and demyelination-like changes, as well as the reduction of the serine/threonine-specific protein kinase (AKT) phosphorylation in DRG neuron-IFRS1 co-cultures exposed to OHP. Zonisamide's neuroprotection against the OHP-induced peripheral sensory neuropathy is possibly mediated by a stimulation of the MEK/ERK and PI3K/AKT signaling pathways and suppression of the p38 MAPK pathway in DRG neurons. Future studies will allow us to solidify zonisamide as a promising remedy against the neurotoxic adverse effects of OHP.
奥沙利铂（OHP）是一种铂类药物，可引起周围神经病，这是一种不良作用，其靶标是背根神经节（DRG）神经元。佐尼沙胺在体外对成年大鼠 DRG 神经元表现出神经保护活性，因此，我们旨在评估其对 OHP 诱导的神经毒性的潜在疗效。佐尼沙胺（100μM）预处理可减轻 OHP（75μM）引起的 DRG 神经元死亡，而与丝裂原活化蛋白激酶（MAPK；MEK/ERK）抑制剂 U0126 或磷脂酰肌醇-3'-磷酸-激酶（PI3K）抑制剂 LY294002 共同孵育则会减弱这种保护作用。佐尼沙胺预处理还可抑制 OHP 诱导的 lined DRG 神经元 ND7/23 中 p38 MAPK 磷酸化，而 p38 MAPK 抑制剂 SB239063（25μM）预处理则可减轻 OHP 诱导的 DRG 神经元死亡。尽管佐尼沙胺未能保护永生化大鼠雪旺细胞 IFRS1 免受 OHP 诱导的细胞死亡，但它可防止轴突变性和脱髓鞘样改变，并防止暴露于 OHP 的 DRG 神经元-IFRS1 共培养物中丝氨酸/苏氨酸特异性蛋白激酶（AKT）磷酸化减少。佐尼沙胺对 OHP 诱导的周围感觉神经病的神经保护作用可能是通过刺激 DRG 神经元中的 MEK/ERK 和 PI3K/AKT 信号通路和抑制 p38 MAPK 通路来介导的。未来的研究将使我们能够确定佐尼沙胺作为对抗 OHP 神经毒性不良反应的有前途的治疗方法。
