Amelioration of Chemotherapy Induced Neuropathic Pain using Novel Nicotinic Acid Derivatives with possible HCN channel binding ability.

Abstract

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_h) 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.