Anti-allodynic effect of Buja in a rat model of oxaliplatin-induced peripheral neuropathy via spinal astrocytes and pro-inflammatory cytokines suppression

Abstract

BackgroundOxaliplatin, a widely used anticancer drug against metastatic colorectal cancer, can induce acute peripheral neuropathy, which is characterized by cold and mechanical allodynia. Activation of glial cells (e.g. astrocytes and microglia) and increase of pro-inflammatory cytokines (e.g. IL-1β and TNF-α) in the spinal cord play a crucial role in the pathogenesis of neuropathic pain. Our previous study demonstrated that Gyejigachulbu-Tang (GBT), a herbal complex formula, alleviates oxaliplatin-induced neuropathic pain in rats by suppressing spinal glial activation. However, it remains to be elucidated whether and how Buja (Aconiti Tuber), a major ingredient of GBT, is involved in the efficacy of GBT.MethodsCold and mechanical allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) in Sprauge-Dawley rats were evaluated by a tail immersion test in cold water (4 °C) and a von Frey hair test, respectively. Buja (300 mg/kg) was orally administrated for five consecutive days after the oxaliplatin injection. Glial activation in the spinal cord was quantified by immunohistochemical staining using GFAP (for astrocytes) and Iba-1 (for microglia) antibodies. The amount of spinal pro-inflammatory cytokines, IL-1β and TNF-α, were measured by ELISA.ResultsSignificant behavioral signs of cold and mechanical allodynia were observed 3 days after an oxaliplatin injection. Oral administration of Buja significantly alleviated oxaliplatin-induced cold and mechanical allodynia by increasing the tail withdrawal latency to cold stimuli and mechanical threshold. Immunohistochemical analysis showed the activation of astrocytes and microglia and the increase of the IL-1β and TNF-α levels in the spinal cord after an oxaliplatin injection. Administration of Buja suppressed the activation of spinal astrocytes without affecting microglial activation and down-regulated both IL-1β and TNF-α levels in the spinal cord.ConclusionsOur results indicate that Buja has a potent anti-allodynic effect in a rat model of oxaliplatin-induced neuropathic pain, which is associated with the inhibition of activation of astrocytes and release of pro-inflammatory cytokines in the spinal cord. Thus, our findings suggest that administration of Buja could be an alternative therapeutic option for the management of peripheral neuropathy, a common side-effect of oxaliplatin.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-017-1556-z) contains supplementary material, which is available to authorized users.

Activation of STAT3-mediated CXCL12 up-regulation in the dorsal root ganglion contributes to oxaliplatin-induced chronic pain

“…Studies also showed that proinflammatory cytokines such as IL-6 play a critical role in STAT3 activation, 24 and oxaliplatin treatment significantly increased proinflammatory cytokines expression in the spinal cord. 25 In this study, we observed that the expressions of p-STAT3, cytokine TNF-α, and IL-1β were persistently upregulated in the DRG following oxaliplatin treatment. It is well known that IL-6-mediated STAT3 activation contributes to chronic inflammatory diseases, autoimmunity, and cancer.…”

The Role of Satellite Glial Cells, Astrocytes, and Microglia in Oxaliplatin-Induced Neuropathic Pain

“…In addition, the observed part also differed from paper to paper, as three studies focused on the DRG [22][23][24], whereas the rest analyzed the change in the spinal cord and the brain. Moreover, three studies observed the acute effect of oxaliplatin [18][19][20], whereas the rest assessed its chronic effect. In this review, we only included studies that conducted in vivo experiments along with glial assessment to better understand the change of glial activation in relation to different states of pain.…”

“…It also prevented the increase in the number of GFAP-positive cells. Jung et al [20] also showed that GFAP-positive cells increased after oxaliplatin administration and that oral administration of Buja (300 mg/kg) significantly decreased the upregulated GFAP-positive cell numbers. In the study by Makker et al [33], although consecutive injection of oxaliplatin significantly induced reduction in paw thresholds on D8, D13, and D16 in C57BL/6J mice, the astrocytic number in the spinal dorsal horn remained unchanged.…”

“…Based on their results, Pacini et al [32] assessed that oxaliplatin did not induce an increase of Iba1 positive cells in the spinal cord but only in the brain areas involved in pain pathways. Jung et al [20] showed that Iba1 positive cells increased after oxaliplatin administration. Oral administration of Buja (300 mg/kg, p.o.)…”

“…By using an animal model of oxaliplatin-induced neuropathic pain [14,15], we have demonstrated that various drugs and treatment methods such as gabapentin [16], duloxetine [5], acupuncture [16], and bee venom [17] can attenuate cold and mechanical hypersensitivity induced by oxaliplatin. Moreover, we have shown that after oxaliplatin injection the activities of spinal astrocytes and microglia increased and that upregulated glial expression was lowered in the group where the pain was attenuated [18][19][20]. Thus, based on the data obtained from other studies and ours, the aim of this review was to understand the role of glia in the development and maintenance of oxaliplatin-induced neuropathic pain and to analyze whether targeting glia could be an effective therapeutic approach.…”