Bertozzi Mariana M, Rossaneis Ana C, Fattori Victor, Longhi-Balbinot Daniela T, Freitas Andressa, Cunha Fernando Q, Alves-Filho José C, Cunha Thiago M, Casagrande Rubia, Verri Waldiceu A
Department of General Pathology, Biological Sciences Center, Londrina State University, Rod. Celso Garcia Cid PR 445, Km 380 Cx. Postal 10.011, 86057-970 Londrina, Parana, Brazil.
Department of Pharmacology, Biological Sciences Center, Londrina State University, Rod. Celso Garcia Cid PR 445, Km 380 Cx. Postal 10.011, 86057-970 Londrina, Parana, Brazil.
Chem Biol Interact. 2017 Aug 1;273:180-189. doi: 10.1016/j.cbi.2017.06.014. Epub 2017 Jun 15.
Injury or dysfunction of somatosensory system induces a complex syndrome called neuropathic pain, which still needs adequate pharmacological control. The current pharmacological treatments were in part developed from natural compounds. Flavonoids are natural polyphenolic molecules presenting varied biological activities and low toxicity. The flavonoid diosmin is a safe compound with good tolerability and low toxicity. This study evaluated the antinociceptive effect of diosmin in the sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain model. Male Swiss mice were submitted to CCI and 7 days after, diosmin at 1 or 10 mg/kg was administrated intraperitoneally. Mechanical (electronic analgesimeter) and thermal (hot plate) hyperalgesia were evaluated 1-24 h after treatment. The role of the NO/cGMP/PKG/KATP channel signaling pathway in the analgesic effect of diosmin was evaluated using the pretreatment with L-NAME (an inhibitor of NOS), ODQ (an inhibitor of soluble guanylate cyclase), KT5823 (an inhibitor of PKG), or glibenclamide (an ATP-sensitive K+ channels blocker). Single treatment with diosmin inhibited in a dose-dependent manner CCI-induced mechanical and thermal hyperalgesia by activating the NO/cGMP/PKG/KATP channel signaling pathway and inhibiting spinal cord cytokine (Il-1β and Il-33/St2) and glial cells activation (microglia - Iba-1, oligodendrocytes - Olig2) mRNA expression markers. Daily treatment during 7 days with diosmin inhibited CCI-induced mechanical and thermal hyperalgesia by inhibiting spinal cord cytokine (Il-1β, Tnfα, and Il-33/St2) and glial cells activation (astrocytes - Gfap, Iba-1, and Olig2) markers mRNA expression. In conclusion, diosmin inhibits neuropathic spinal cord nociceptive mechanisms suggesting this flavonoid as a potential therapeutic molecule to reduce nerve lesion-induced neuropathic pain.
躯体感觉系统的损伤或功能障碍会引发一种名为神经性疼痛的复杂综合征，而这种疼痛仍需要适当的药物控制。目前的药物治疗部分是基于天然化合物研发的。黄酮类化合物是具有多种生物活性且低毒的天然多酚分子。黄酮类化合物地奥司明是一种安全性良好、耐受性佳且毒性低的化合物。本研究评估了地奥司明在坐骨神经慢性缩窄损伤（CCI）诱导的神经性疼痛模型中的镇痛作用。雄性瑞士小鼠接受CCI手术，7天后，腹腔注射1或10 mg/kg的地奥司明。在治疗后1 - 24小时评估机械性（电子镇痛仪）和热性（热板）痛觉过敏。通过用L - NAME（一种一氧化氮合酶抑制剂）、ODQ（一种可溶性鸟苷酸环化酶抑制剂）、KT5823（一种蛋白激酶G抑制剂）或格列本脲（一种ATP敏感性钾通道阻滞剂）进行预处理，评估NO/cGMP/PKG/KATP通道信号通路在地奥司明镇痛作用中的作用。单次给予地奥司明通过激活NO/cGMP/PKG/KATP通道信号通路并抑制脊髓细胞因子（Il - 1β和Il - 33/St2）以及胶质细胞活化（小胶质细胞 - Iba - 1、少突胶质细胞 - Oligo2）的mRNA表达标志物，以剂量依赖性方式抑制CCI诱导的机械性和热性痛觉过敏。连续7天每日给予地奥司明通过抑制脊髓细胞因子（Il - 1β、Tnfα和Il - 33/St2）以及胶质细胞活化（星形胶质细胞 - Gfap、Iba - 1和Oligo2）标志物的mRNA表达，抑制CCI诱导的机械性和热性痛觉过敏。总之，地奥司明抑制神经性脊髓伤害性感受机制，表明这种黄酮类化合物是一种潜在的治疗分子，可减轻神经损伤诱导的神经性疼痛。
