Botulinum toxin type A alleviates neuropathic pain and suppresses inflammatory cytokines release from microglia by targe
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Cell & Bioscience Open Access
RESEARCH
Botulinum toxin type A alleviates neuropathic pain and suppresses inflammatory cytokines release from microglia by targeting TLR2/MyD88 and SNAP23 Xuan Wang1†, Sheng Tian1†, Hansen Wang1, Pan Liu1, Heqing Zheng1, Lanxiang Wu1, Qian Liu2* and Wei Wu1*
Abstract Background: Botulinum toxin type A (BTX-A) was considered to be a new potential drug for neuropathic pain (NP) treatment. Results: In vivo, BTX-A attenuated chronic compression injury (CCI)-induced pain in rats, and reduced production of pro-inflammatory factors. The inhibition of BTX-A to expression and phosphorylation of SNAP23 were partly reversed by TLR2/MyD88 upregulation. In LPS-stimulated microglia, we also found that BTX-A suppressed TLR2, MyD88, p-SNAP23 and SNAP23 expression, and reduced pro-inflammatory factors secretion. Upregulation of TLR2 and MyD88 recued the inhibition of BTX-A to LPS-induced activation of SNAP23. Then, we demonstrated that BTX-A reduced expression of SNAP23 through inhibition of IKKα/β phosphorylation. Besides, the inhibition of BTX-A to LPS-induced upregulation of SNAP23 can be reversed by proteasome inhibitor. NEDD4, an E3 ubiquitin ligase, was proved to be bind with SNAP23. BTX-A reduced expression of SNAP23 via facilitating ubiquitin-mediated degradation of SNAP23. Conclusion: Overall, our data demonstrated that BTX-A attenuated NP via reducing the secretion of pro-inflammatory factors from microglia by inhibition of TLR2/MyD88 signaling. BTX-A downregulated expression of SNAP23 via reducing phosphorylation of IKKα/β, and enhancing ubiquitination of SNAP23 by suppressing TLR2/MyD88 signaling. Keywords: Neuropathic pain, Botulinum toxin type A, Microglia, Synaptosome associated protein 23 Background Neuropathic pain (NP) is a pain syndrome characterized by the spontaneously intermittent or ongoing burning pain, allodynia and hyperalgesia. NP resulted from the nervous system damage induced by trauma (such as brain injury and spinal) and multiple disorders (such as malignant tumors, stroke and diabetics) [1]. According to the research of epidemiological, NP affects approximately *Correspondence: [email protected]; [email protected] † Xuan Wang and Sheng Tian are Co-first authors 1 Department of Neurology, The Second Affiliated Hospital of Nanchang University, No.1 Minde Road, NanchangJiangxi Province 330006, China 2 Imaging Department, The Second Affiliated Hospital of Nanchang University, NanchangJiangxi Province 330006, China
6.9–10% population. Medical expense of NP is increasing year by year. NP becomes a major public health problem in the world, and a global burden of medical systems [2]. Nevertheless, NP usually companied with an unsatisfactory treatment outcome due to partly drugs not suitable to europathic pain, and in primary care, the contribution of neuropathy to pain was unrecognized [3]. At present, numerous new compounds for NP treatment are in preclinical development. For example, serotonin modulators, vanilloid receptor antagonists and inhibitor of apoptosis [
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