Abstract
Vincristine is a toxic chemotherapeutic agent which often triggers neuropathic pain through inflammation. Morin isolated from figs (Ficus carica) exerts anti-inflammatory and neuroprotective activities. We investigated whether morin ameliorates vincristine-induced neuropathic pain and the underlying mechanism. Vincristine was injected i.p. for 10 days (day 1–5 and day 8–12). Morin was orally administered every other day from day 1 to 21. The pain behaviors were determined by measuring paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The axons of sciatic nerves were stained with toluidine blue to study the histological abnormality. Function deficit of sciatic nerves was evaluated by sciatic functional index and the sciatic nerve conduction velocity. Neuronal excitability was assessed electrophysiologically and inflammatory mediators were detected using western blotting in dorsal root ganglia. The vincristine-induced reduction in PWT, PWL, and body weight gain was attenuated by morin. Morin restored the sciatic nerve deficits both histologically and functionally in vincristine-injected rats. The vincristine-induced neuronal hyperexcitability and increase in the expression of IL-6, NF-κB, and pNF-κB were abolished after morin administration. This study suggests that morin treatment suppressed vincristine-induced neuropathic pain by protecting the sciatic nerve and inhibiting inflammation through NF-κB pathway.
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References
Asato F, Butler M, Blomberg H, Gordh T (2000) Variation in rat sciatic nerve anatomy: implications for a rat model of neuropathic pain. J Peripher Nerv Syst 5:19–21
Bachewal P, Gundu C, Yerra VG, Kalvala AK, Areti A, Kumar A (2018) Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy. BioFactors 44:109–122. https://doi.org/10.1002/biof.1397
Bain JR, Mackinnon SE, Hunter DA (1989) Functional evaluation of complete sciatic, peroneal, and posterior tibial nerve lesions in the rat. Plast Reconstr Surg 83:129–138
Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63
Chen J-Y, Chu L-W, Cheng K-I, Hsieh S-L, Juan Y-S, Wu B-N (2018) Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model. Sci Rep 8:16457. https://doi.org/10.1038/s41598-018-34915-5
Chien L-Y, Cheng J-K, Chu D, Cheng C-F, Tsaur M-L (2007) Reduced expression of A-type potassium channels in primary sensory neurons induces mechanical hypersensitivity. J Neurosci 27:9855–9865. https://doi.org/10.1523/jneurosci.0604-07.2007
Devor M (2009) Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res 196:115–128. https://doi.org/10.1007/s00221-009-1724-6
Ducut Sigala JL, Bottero V, Young DB, Shevchenko A, Mercurio F, Verma IM (2004) Activation of transcription factor NF-kappaB requires ELKS, an IkappaB kinase regulatory subunit. Science 304:1963–1967. https://doi.org/10.1126/science.1098387
Fan L et al (2014) Impaired neuropathic pain and preserved acute pain in rats overexpressing voltage-gated potassium channel subunit Kv1.2 in primary afferent neurons. Mol Pain 10(1):8
Fang S-H, Hou Y-C, Chang W-C, Hsiu S-L, Chao P-DL, Chiang B-L (2003) Morin sulfates/glucuronides exert anti-inflammatory activity on activated macrophages and decreased the incidence of septic shock. Life Sci 74:743–756
Gautam M, Ramanathan M (2018) Saponins of Tribulus terrestris attenuated neuropathic pain induced with vincristine through central and peripheral mechanism. Inflammopharmacology. https://doi.org/10.1007/s10787-018-0502-0
Geis C, Beyreuther BK, Stöhr T, Sommer C (2011) Lacosamide has protective disease modifying properties in experimental vincristine neuropathy. Neuropharmacology 61:600–607. https://doi.org/10.1016/j.neuropharm.2011.05.001
Ghosh S, May MJ, Kopp EB (1998) NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 16:225–260. https://doi.org/10.1146/annurev.immunol.16.1.225
Hu L-Y, Mi W-L, Wu G-C, Wang Y-Q, Mao-Ying Q-L (2019) Prevention and treatment for chemotherapy-induced peripheral neuropathy: therapies based on CIPN mechanisms. Curr Neuropharmacol 17:184–196. https://doi.org/10.2174/1570159x15666170915143217
Jiang W, Wang Y, Sun W, Zhang M (2017) Morin suppresses astrocyte activation and regulates cytokine release in bone cancer pain rat models. Phytother Res 31:1298–1304. https://doi.org/10.1002/ptr.5849
Kapoor R, Kakkar P (2012) Protective role of morin, a flavonoid, against high glucose induced oxidative stress mediated apoptosis in primary rat hepatocytes. PLoS ONE 7:e41663. https://doi.org/10.1371/journal.pone.0041663
Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621–663. https://doi.org/10.1146/annurev.immunol.18.1.621
Kiguchi N, Maeda T, Kobayashi Y, Saika F, Kishioka S (2009) Involvement of inflammatory mediators in neuropathic pain caused by vincristine. Int Rev Neurobiol 85:179–190. https://doi.org/10.1016/s0074-7742(09)85014-9
Kroner A, Schwab N, Ip CW, Sommer C, Wessig C, Wiendl H, Martini R (2009) The co-inhibitory molecule PD-1 modulates disease severity in a model for an inherited, demyelinating neuropathy. Neurobiol Dis 33:96–103. https://doi.org/10.1016/j.nbd.2008.09.021
Lin MJ-Y, Paul MR, Kuo DJ (2018) Severe neuropathic pain with concomitant administration of vincristine and posaconazole. J Pediatr Pharmacol Ther 23:417–420. https://doi.org/10.5863/1551-6776-23.5.417
Manna SK, Aggarwal RS, Sethi G, Aggarwal BB, Ramesh GT (2007) Morin (3,5,7,2′,4′-Pentahydroxyflavone) abolishes nuclear factor-kappaB activation induced by various carcinogens and inflammatory stimuli, leading to suppression of nuclear factor-kappaB-regulated gene expression and up-regulation of apoptosis. Clin Cancer Res 13:2290–2297. https://doi.org/10.1158/1078-0432.ccr-06-2394
Park HJ (2014) Chemotherapy induced peripheral neuropathic pain. Korean J Anesthesiol 67:4–7. https://doi.org/10.4097/kjae.2014.67.1.4
Schomberg D, Ahmed M, Miranpuri G, Olson J, Resnick DK (2012) Neuropathic pain: role of inflammation, immune response, and ion channel activity in central injury mechanisms. Ann Neurosci 19:125–132. https://doi.org/10.5214/ans.0972.7531.190309
Sharma SH, Kumar JS, Chellappan DR, Nagarajan S (2018) Molecular chemoprevention by morin—a plant flavonoid that targets nuclear factor kappa B in experimental colon cancer. Biomed Pharmacother 100:367–373. https://doi.org/10.1016/j.biopha.2018.02.035
Sommer C, Kress M (2004) Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 361:184–187. https://doi.org/10.1016/j.neulet.2003.12.007
Steinman L (1996) Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85:299–302
Tanner KD, Levine JD, Topp KS (1998) Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat. J Comp Neurol 395:481–492
Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783. https://doi.org/10.1038/nature01786
Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S (1995) Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev 9:2723–2735
Verstappen CCP et al (2005) Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening. Neurology 64:1076–1077. https://doi.org/10.1212/01.wnl.0000154642.45474.28
Wang Y et al (2018) Sensitization of TRPV1 receptors by TNF-α orchestrates the development of vincristine-induced pain. Oncol Lett 15:5013–5019. https://doi.org/10.3892/ol.2018.7986
Xiao WH, Bennett GJ (2008) Chemotherapy-evoked neuropathic pain: abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-L-carnitine. Pain 135:262–270. https://doi.org/10.1016/j.pain.2007.06.001
Zhao J-Y et al (2017) DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nat Commun 8:14712. https://doi.org/10.1038/ncomms14712
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Ke Jiang and Jinshan Shi: Performed the experiments and analyzed the data. Jing Shi: Designed the study and wrote the manuscript. All authors approved the final submission.
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Jiang, K., Shi, J. & Shi, J. Morin Alleviates Vincristine-Induced Neuropathic Pain via Nerve protective Effect and Inhibition of NF-κB Pathway in Rats. Cell Mol Neurobiol 39, 799–808 (2019). https://doi.org/10.1007/s10571-019-00679-3
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DOI: https://doi.org/10.1007/s10571-019-00679-3