Small-molecule natural product sophoricoside reduces peripheral neuropathic pain via directly blocking of NaV1.6 in dorsal root ganglion nociceptive neurons

Weijie Guo; Haoyi Yang; Yuwei Wang; Tao Liu; Yunping Pan; Xiying Chen; Qiuyin Xu; Dizhou Zhao; Zhiming Shan; Song Cai

doi:10.1038/s41386-024-01998-w

Small-molecule natural product sophoricoside reduces peripheral neuropathic pain via directly blocking of NaV1.6 in dorsal root ganglion nociceptive neurons

Neuropsychopharmacology. 2024 Oct 16. doi: 10.1038/s41386-024-01998-w. Online ahead of print.

Authors

Weijie Guo^#¹, Haoyi Yang^#², Yuwei Wang¹, Tao Liu¹, Yunping Pan³, Xiying Chen², Qiuyin Xu², Dizhou Zhao², Zhiming Shan^{4

5}, Song Cai⁶

Affiliations

¹ Health Science Center, Shenzhen University, Shenzhen, China.
² Department of Anesthesiology, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.
³ Department of Periodontology & Oral Mucosa, Shenzhen Stomatology Hospital, Shenzhen, China.
⁴ Department of Anesthesiology, Shenzhen People's Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China. shanzhm@mail2.sysu.edu.cn.
⁵ Laboratory and Clinical Research Institute for Pain, Department of Anaesthesiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. shanzhm@mail2.sysu.edu.cn.
⁶ Health Science Center, Shenzhen University, Shenzhen, China. caisong@szu.edu.cn.

^# Contributed equally.

PMID: 39414988
DOI: 10.1038/s41386-024-01998-w

Abstract

Peripheral neuropathic pain poses a significant global health challenge. Current drugs for peripheral neuropathic pain often fall short in efficacy or come with severe side effects, emphasizing the critical need for the development of highly effective and well-tolerated alternatives. Sophoricoside (SOP) is a nature product-derived isoflavone that possesses various pharmacological effects on inflammatory and neuropathy diseases. Here, in this study, analgesic effect was investigated by intrathecally administration of SOP/vehicle to spared nerve injury (SNI) or paclitaxel-induced peripheral neuropathic pain (PINP) rodent models, and mechanical allodynia was measured in Von Frey tests. Ipsilateral L4-L6 dorsal root ganglia (DRG) were used for protein expression. In silico molecular docking analysis was applied for assessing compound-target binding affinity. Primary cultured DRG neurons were utilized to investigate SOP's effect on veratridine-triggered nociceptor activities and its selective inhibition of voltage-gated sodium channels subtype 1.6 (NaV1.6). The results showed SOP treatment alleviated mechanical allodynia in SNI and PINP rodent models (paw withdrawal threshold after 1 h of injection: SNI-vehicle: 1.385 ± 0.338 g; SNI-SOP: 9.963 ± 2.029 g, P < 0.001; PINP-vehicle: 5.040 ± 0.985 g; PINP-SOP: 8.287 ± 3.812 g, P = 0.004). SOP presented effects on both inhibiting veratridine-triggered nociceptor activities (oscillatory population: vehicle: 39.9 ± 7.3%; SOP: 30.7 ± 9.8%, P = 0.021) and selectively blocking NaV1.6 in DRG sensory neurons. Molecular docking analysis indicated direct binding between SOP and NaV1.6, leading to its endocytosis in DRG Sensory Neurons. In conclusion, SOP alleviated nociceptive allodynia induced by peripheral nerve injury via selectively blocking of NaV1.6 in DRG nociceptive neurons. we highlight its potential as an analgesic and elucidate its mechanism involving NaV1.6 endocytosis. This research opens avenues for exploring the analgesic effects of SOP and its potential impact on neuropathic pain therapy.

Abstract

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