Background: Oxaliplatin can induce peripheral neuropathy (OXIPN) as an adverse side effect in cancer patients.\nUntil now, no effective preventive or therapeutic drug has been developed; therefore, the dose-limiting factor of\nOXIPN is still an obstacle in the use of oxaliplatin to treat cancer patients. In the present study, we report for the\nfirst time that the aqueous extract of Lithospermi radix (WLR) can attenuate the OXIPN in both in vitro and in vivo\nneuropathic models.\nMethods: The protective effect of WLR on OXIPN was evaluated in vitro by quantifying nerve growth factor (NGF)-\nstimulated neurite outgrowth in PC12 cells treated with a combination of oxaliplatin and WLR. The neuroprotective\npotential of WLR was further confirmed by measuring the changes in nociceptive sensitivities to external mechanical\nstimuli in neuropathic animals induced by oxaliplatin. Histological and immunohistochemical studies were further done\nto examine the effect of WLR in mouse spinal cords and footpads.\nResults: Oxaliplatin-induced neurotoxicity in NGF-stimulated PC12 cells. It could reduce the lengths and branching\nnumbers of neuritis in NGF-stimulated PC12 cells. Co-treatment of WLR rescued the differentiated PC12 cells from\nthe neurotoxicity of oxaliplatin. In a chronic OXIPN animal model, administration of oxaliplatin i.p. induced enhanced\nnociceptive sensitivity to mechanical stimuli (25.0 to 72.5 % of response rate) along with spinal activation of microglias\nand astrocytes and loss of intraepidermal nerve fibers in footpads, which is remarkably suppressed by oral administration\nof WLR (67.5 to 35 % of response rate at the end of experiment). Cytotoxicity of oxaliplatin determined in human cancer\ncells was not affected irrespective of the presence of WLR.\nConclusions: In conclusion, we demonstrated that WLR can attenuate OXIPN in both in vitro and in vivo experimental\nmodels, which may be in part attributed to its anti-inflammatory activity in the spinal cord and its neuroprotective\npotential in the peripheral nerve system without affecting the anti-tumor potential of oxaliplatin. Therefore, WLR could\nbe considered as a good starting material to develop a novel therapeutic agent targeting OXIPN. However, further\nstudies should be done to elucidate the underlying mechanism such as molecular targets and active constituent(s) in\nWLR with neuroprotective potential.
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