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

Molecular neurobiology 2025

["Saini A", "Sharma S", "Rana P", "Khanna B", "Kaur T", "Dhingra N"]

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 (Ih) 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.

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