Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Cistanche tubulosa phenylethanol glycoside liposome ameliorates oxaliplatin-induced peripheral neuropathy by promoting RNA N6-methyladenosine modification.
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Li Yatan, Ma Xuexian, Zeng Yujie, Zhang Shilei, Zhang Wei, Kuerban Munire, Yang Fan, Wang Ziyi
Аннотация
BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) is a frequent dose-limiting toxicity in cancer treatment, with no effective FDA-approved therapy available. Dysregulated RNA N6-methyladenosine (m6A) modification and impaired PI3K/AKT signaling have been implicated in neuronal injury and regeneration. Phenylethanol glycosides (CPhGs), the main bioactive compounds of Cistanche tubulosa, possess neuroprotective and anti-inflammatory properties, but their role in OIPN remains unclear. The current research aims to investigate the potential therapeutic effect in OIPN.
METHODS: Mice were treated with oxaliplatin to induce OIPN, followed by treatment with CPhG or duloxetine. Behavioral tests (Y-maze, von Frey, Hargreaves), electrophysiology (CMAP, SNAP), immunostaining, qPCR, and western blotting were performed to assess neuronal function and molecular changes. In addition, primary DRG neuron culture was treated with oxaliplatin with or without CPhG to evaluate cell survival, neurite outgrowth, and apoptosis. Bioinformatic analysis was conducted to identify target pathways.
RESULTS: CPhG significantly ameliorated oxaliplatin-induced motor deficits and sensory hypersensitivity in a dose-dependent manner, comparable to or exceeding duloxetine. Electrophysiological measurements confirmed restoration of CMAP and SNAP. Mechanistically, CPhG suppressed IL-6 expression and partially restored NeuN levels in DRG neurons. Importantly, CPhG enhanced PI3K/AKT signaling and increased m6A RNA methylation by upregulating methyltransferases (Mettl3, Mettl14) and downregulating demethylase FTO. In vitro, CPhG promoted DRG neuronal survival, neurite outgrowth, and reduced apoptosis, consistent with AKT activation and m6A modification.
CONCLUSIONS: CPhG alleviates oxaliplatin-induced peripheral neuropathy by dual mechanisms: reducing neuroinflammation via IL-6 suppression and promoting neuronal survival and regeneration through AKT activation and m6A-dependent epitranscriptomic regulation. Compared with duloxetine, CPhG demonstrated superior neuroprotective and anti-inflammatory effects, supporting its potential as a novel therapeutic agent for OIPN.
METHODS: Mice were treated with oxaliplatin to induce OIPN, followed by treatment with CPhG or duloxetine. Behavioral tests (Y-maze, von Frey, Hargreaves), electrophysiology (CMAP, SNAP), immunostaining, qPCR, and western blotting were performed to assess neuronal function and molecular changes. In addition, primary DRG neuron culture was treated with oxaliplatin with or without CPhG to evaluate cell survival, neurite outgrowth, and apoptosis. Bioinformatic analysis was conducted to identify target pathways.
RESULTS: CPhG significantly ameliorated oxaliplatin-induced motor deficits and sensory hypersensitivity in a dose-dependent manner, comparable to or exceeding duloxetine. Electrophysiological measurements confirmed restoration of CMAP and SNAP. Mechanistically, CPhG suppressed IL-6 expression and partially restored NeuN levels in DRG neurons. Importantly, CPhG enhanced PI3K/AKT signaling and increased m6A RNA methylation by upregulating methyltransferases (Mettl3, Mettl14) and downregulating demethylase FTO. In vitro, CPhG promoted DRG neuronal survival, neurite outgrowth, and reduced apoptosis, consistent with AKT activation and m6A modification.
CONCLUSIONS: CPhG alleviates oxaliplatin-induced peripheral neuropathy by dual mechanisms: reducing neuroinflammation via IL-6 suppression and promoting neuronal survival and regeneration through AKT activation and m6A-dependent epitranscriptomic regulation. Compared with duloxetine, CPhG demonstrated superior neuroprotective and anti-inflammatory effects, supporting its potential as a novel therapeutic agent for OIPN.