Department of Pharmacy, University of Peshawar, Peshawar, 25120, Pakistan.
Department of Pharmacy, Cecos University of Science and Technology, Peshawar, Pakistan.
Neurochem Int. 2021 Mar;144:104981. doi: 10.1016/j.neuint.2021.104981. Epub 2021 Feb 5.
Paclitaxel is an anti-microtubule agent, most widely used chemotherapeutic agent for the treatment of malignant solid tumors. However, it is associated with some severe side effects including painful neurotoxicity with reporting of neuropathic pain and sensory abnormalities by patients during and after paclitaxel therapy. Peripheral neuropathy was induced by the administration of paclitaxel (4 mg/kg on days 1, 3, 5, and 7). In this study, the anti-nociceptive and anti-inflammatory propensity of 3-Hydroxyflavone (3HF) in mice and the preventive effect of 3HF against paclitaxel-induced peripheral neuropathy in Sprague Dawley (SD) rats were investigated. Moreover, tactile and cold allodynia, thermal and tail immersion hyperalgesia, and effects on motor-coordination were also evaluated. Furthermore, the expression of proinflammatory cytokines i.e. Calcitonin gene-related peptide (CGRP), and Substance P from the spinal cord was examined through RT-PCR. Additionally, a computational structural biology approach was applied to search the potential therapeutic targets and to predict the binding mechanism of 3HF. Treatment of 3HF alleviated the nociceptive pain, paw edema, development of tactile and cold allodynia, and hyperalgesia. Similarly, treatment with 3HF suppressed the paclitaxel-induced increase in mRNA expression of several inflammatory cytokines including tumor necrosis factor -α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), CGRP, and Substance P. However, the daily treatment of 3HF did not affect the motor behaviors of rats. The inhibitory mechanism of 3HF in neuropathic pain is predicted with extensive computational bioinformatics approach which indicates that the 3HF effectively interacts with the binding domains of Nuclear factor-kappa B (NF-κB), CGRP receptor and the receptor of Substance P to exert its inhibitory activities. However, the computationally predicted binding affinities revealed that the potential of binding of the compound with Substance P receptor (Neurokinin 1 receptor) is higher than the other receptors; there NK1R could be the most possible binding target of 3HF. These findings indicate that 3HF has anti-nociceptive, anti-inflammatory, and anti-neuropathic pain effects against paclitaxel-induced neuropathic pain.
紫杉醇是一种抗微管药物，是治疗恶性实体肿瘤最广泛使用的化疗药物。然而，它与一些严重的副作用有关，包括疼痛性神经毒性，患者在紫杉醇治疗期间和之后会报告神经病理性疼痛和感觉异常。外周神经病变是由紫杉醇给药引起的（第 1、3、5 和 7 天 4mg/kg）。在这项研究中，研究了 3-羟基黄酮（3HF）在小鼠中的镇痛和抗炎倾向，以及 3HF 对 Sprague Dawley（SD）大鼠紫杉醇诱导的周围神经病变的预防作用。此外，还评估了触觉和冷感觉过敏、热和尾巴浸入性痛觉过敏以及对运动协调的影响。此外，还通过 RT-PCR 检查了脊髓中促炎细胞因子即降钙素基因相关肽（CGRP）和 P 物质的表达。此外，还应用计算结构生物学方法来搜索潜在的治疗靶点，并预测 3HF 的结合机制。3HF 的治疗减轻了疼痛性疼痛、爪水肿、触觉和冷感觉过敏以及痛觉过敏的发展。同样，3HF 的治疗抑制了紫杉醇诱导的几种炎症细胞因子包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）、CGRP 和 P 物质的 mRNA 表达增加。然而，3HF 的每日治疗并未影响大鼠的运动行为。通过广泛的计算生物信息学方法预测了 3HF 在神经病理性疼痛中的抑制机制，表明 3HF 有效地与核因子-κB（NF-κB）、CGRP 受体和 P 物质受体的结合域相互作用，发挥其抑制活性。然而，计算预测的结合亲和力表明，该化合物与 P 物质受体（神经激肽 1 受体）的结合潜力高于其他受体；因此，NK1R 可能是 3HF 的最可能结合靶标。这些发现表明，3HF 对紫杉醇诱导的神经病理性疼痛具有镇痛、抗炎和抗神经病理性疼痛作用。
