Gyejigachulbu‐Tang Relieves Oxaliplatin‐Induced Neuropathic Cold and Mechanical Hypersensitivity in Rats via the Suppression of Spinal Glial Activation

Abstract

Activation of spinal glial cells plays a crucial role in the pathogenesis of neuropathic pain. An administration of oxaliplatin, an important anticancer drug, often induces acute neuropathic cold hypersensitivity and/or mechanical hypersensitivity in patients. Gyejigachulbu-tang (GBT), a herbal formula comprising Cinnamomi Cortex, Paeoniae Radix, Atractylodis Lanceae Rhizoma, Zizyphi Fructus, Glycyrrhizae Radix, Zingiberis Rhizoma, and Aconiti Tuber, has been used in East Asia to treat various pain symptoms, especially in cold patients. This study investigated whether and how GBT alleviates oxaliplatin-induced cold and mechanical hypersensitivity in rats. The behavioral signs of cold and mechanical hypersensitivity were evaluated by a tail immersion test in cold water (4°C) and a von Frey hair test, respectively. The significant cold and mechanical hypersensitivity were observed 3 days after an oxaliplatin injection (6 mg/kg, i.p.). Daily oral administration of GBT (200, 400, and 600 mg/kg) for 5 days markedly attenuated cold and mechanical hypersensitivity. Immunoreactivities of glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker) in the spinal dorsal horn were significantly increased by an oxaliplatin injection, which were restored by GBT administration. These results indicate that GBT relieves oxaliplatin-induced cold and mechanical hypersensitivity in rats possibly through the suppression of spinal glial activation.

Therapeutic Effects of Phytochemicals and Medicinal Herbs on Chemotherapy-Induced Peripheral Neuropathy

“…In our experiment, oral administration of Gyejigachulbu-Tang (200, 400, and 600 mg/kg for 5 days) markedly ameliorated mechanical-and cold-allodynia induced by oxaliplatin treatment. The formula possibly functions through the suppression of spinal glial activation [36]. We confirmed that the extract of Aconiti tuber could attenuate both cold and mechanical allodynia similar to Gyejigachulbu-Tang treatment.…”

“…Oxaliplatin in rats Attenuates cold and mechanical allodynia Suppresses spinal glia activation [36] Gyeryongtongrac-Bang…”

The Inhibition by Oxaliplatin, a Platinum-Based Anti-Neoplastic Agent, of the Activity of Intermediate-Conductance Ca2+-Activated K+ Channels in Human Glioma Cells

“…This study prompts us to propose that, assuming that similar findings observed in this study occur in glial or glioma cells in vivo, any changes in the magnitude of functional [13,42]. Whether the activators of IK Ca channels or/and suppression of gap junction channels are effective at alleviating OXAL-induced neurotoxicity [23,34,41,43] necessitates further investigation.…”

“…OXALinduced inhibition of IK Ca -channel activity may be attributed to an interaction of the oxalate group embedded in this molecule with free Ca 2+ ions [42]. OXAL and its structurally related compounds would be intriguing pharmacological or toxicological tools used to characterize the IK Ca channels.…”

“…In OXAL-preincubated cells, addition of TRAM-34 was unable to suppress I K amplitude in 13-06-MG cells. Therefore, the mode of inhibitory action on IK Ca channels and cell proliferation is necessarily linked to an interaction of the OXAL molecule with free Ca 2+ ions [42], although it can adduct with DNAs that lead to cell death and intracellular generation of reactive oxygen species following the crosslinking with DNAs [18,24,25].…”