The ethyl acetate extract of Schefflera kwangsiensis ameliorates oxaliplatin-induced peripheral neuropathic pain by activation of SERCA2b

The chemotherapeutic agent oxaliplatin (OXA) can lead to OXA-induced peripheral neuropathy (OIPN). As a calcium transporter, sarco/endoplasmic reticulum Ca^{2 +} -ATPase (SERCA) facilitates the movement of Ca^{2 +} from the cytoplasm into endoplasmic reticulum (ER). Schefflera kwangsiensis Merr. ex H.L. Li (SKM) is traditionally used for conditions like trigeminal neuralgia and sciatica, with its active components known as potent SERCA activators. An OIPN model was established by i.p. 4 mg/kg OXA on days 1, 2, 8, 9, 15, and 16. mRNA and protein expression of SERCA2b in the dorsal root ganglion (DRG) were detected using qPCR and immunofluorescence. Mechanical pain sensitivity in OIPN was assessed by Von Frey test, the excitability of DRG neurons was evaluated by whole-cell current clamp and patch clamp, Oxidative stress and neuronal apoptosis/necrosis was detected by the reactive oxygen species (ROS)-specific probe, H₂DCFDA and FITC/PI. This study investigates SERCA2b as a novel target for treating OIPN. We observed that during the progression of OIPN, SERCA2b mRNA and protein levels significantly decreased. Treatment with the SERCA agonist CDN1163 and the ethyl acetate extract of SKM (SKM.Ext), alongside duloxetine, improved neuronal pathology and restored DRG neuron diameter while decreasing inflammatory markers Il-1β and Tnf-α. 1-h pre-incubation with CDN1163 and SKM.Ext significantly reduced hyperexcitability in DRG neurons exposed to OXA, suggesting that SERCA agonists inhibited the OXA-induced VGSC abnormal increase in DRG VGSC current density. The inhibition of oxidative stress using Nacetyl-L-cysteine (NAC) significantly improves SERCA expression in OIPN. Our findings indicate that oxidative stress from OIPN reduces SERCA2b expression in DRG, CDN1163 and Schefflera kwangsiensis enhances SERCA2b levels in DRG neurons, and reduces neuronal sensitization resulting in alleviating OIPN. Our study shows that activation of SERCA2b via CDN1163 or Schefflera kwangsiensis extract can alleviate neuropathic pain, which expand the clinical analgesic indications of Schefflera kwangsiensis, and support the development of SERCA-targeting therapies as promising strategies for managing OXA-induced neuropathy.