Saini Akash, Sharma Shiwani, Rana Priyanka, Khanna Bhawna, Kaur Tanzeer, Dhingra Neelima
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
Department of Biophysics, Panjab University, Chandigarh, 160014, India.
Mol Neurobiol. 2025 Jun 12. doi: 10.1007/s12035-025-05088-w.
One of the major debilitating side effects of cancer chemotherapy is neuropathic pain, which results from abnormal neural signaling and significantly diminishes patients' quality of life. Paclitaxel (PT), a widely used chemotherapeutic agent, induces peripheral nerve degeneration, leading to the development of painful neuropathy. In this study, PT was used to establish a mouse model of chemotherapy-induced peripheral neuropathy. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a key role in regulating neuronal pacemaker activity. The HCN current (I) promotes repetitive firing in nociceptive neurons, contributing to neuropathic pain. We synthesized a series of novel compounds and investigated their molecular interactions with HCN1 using docking studies based on a homology model of the channel's open pore. Pharmacokinetic predictions were subsequently performed to identify potential HCN1 inhibitors. Among the synthesized compounds, 3'-4'-dimethylphenyl pyridine-3-carboxylate (NDAK-6) showed strong binding affinity for HCN1. In vitro cell viability assays using the SH-SY5Y cell line revealed that NDAK-6 exhibited lower cytotoxicity than ivabradine, a known HCN inhibitor. NDAK-6 was further evaluated in vivo in the PT-induced neuropathic pain model, where it significantly reduced pain-like behaviors, including thermal hyperalgesia and mechanical allodynia. Moreover, it attenuated the expression of inflammatory markers TNF-α, NF-κB, p53, and PKC-δ in the thalamus, as well as NF-κB and p53 in dorsal root ganglion (DRG) neurons. These findings suggest that NDAK-6 may be a promising therapeutic candidate for chemotherapy-induced neuropathic pain.
癌症化疗的主要致残副作用之一是神经性疼痛，它由异常的神经信号传导引起，会显著降低患者的生活质量。紫杉醇（PT）是一种广泛使用的化疗药物，会导致周围神经变性，进而引发疼痛性神经病变。在本研究中，PT被用于建立化疗诱导的周围神经病变小鼠模型。超极化激活的环核苷酸门控（HCN）通道在调节神经元起搏器活动中起关键作用。HCN电流（I）促进伤害性神经元的重复放电，导致神经性疼痛。我们合成了一系列新型化合物，并基于通道开放孔的同源模型，通过对接研究来探究它们与HCN1的分子相互作用。随后进行了药代动力学预测，以识别潜在的HCN1抑制剂。在合成化合物中，3'-4'-二甲基苯基吡啶-3-羧酸酯（NDAK-6）对HCN1表现出强烈的结合亲和力。使用SH-SY5Y细胞系进行的体外细胞活力测定表明，NDAK-6的细胞毒性低于已知的HCN抑制剂伊伐布雷定。NDAK-6在PT诱导的神经性疼痛模型中进行了进一步的体内评估，结果显示它能显著减轻疼痛样行为，包括热痛觉过敏和机械性异常性疼痛。此外，它还减弱了丘脑中炎症标志物TNF-α、NF-κB、p53和PKC-δ的表达，以及背根神经节（DRG）神经元中NF-κB和p53的表达。这些发现表明，NDAK-6可能是化疗诱导的神经性疼痛的一种有前景的治疗候选药物。
