Khan Jawad, Ali Gowhar, Saeed Aamer, Khurshid Asma, Ahmad Sajjad, Kashtoh Hamdy, Ataya Farid S, Bathiha Gaber El-Saber, Ullah Aman, Khan Ajmal
Department of Pharmacy, University of Peshawar, Peshawar 25120, Pakistan.
Department of Chemistry, Quaid-I-Azam University Islamabad 45320, Pakistan.
Eur J Pharm Sci. 2024 Jul 1;198:106797. doi: 10.1016/j.ejps.2024.106797. Epub 2024 May 11.
The multicomponent etiology, complex clinical implications, dose-based side effect and degree of pain mitigation associated with the current pharmacological therapy is incapable in complete resolution of chronic neuropathic pain patients which necessitates the perpetual requirement of novel medication therapy. Therefore, this study explored the ameliorative aptitude of two novel methanimine imitative like (E)-N-(4-nitrobenzylidene)-4‑chloro-2-iodobenzamine (KB 09) and (E)-N-(4-methylbenzylidene)-4‑chloro-2-iodobenzamine (KB 10) in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rat model. Standard behavioral tests like dynamic and static allodynia, cold, thermal and mechanical hyperalgesia along with rotarod activity were performed at various experimental days like 0, 3, 7, 14 and 21. Enzyme linked immunosorbent assay (ELISA) on spinal tissue and antioxidant assays on sciatic nerve were executed accompanied by molecular docking and simulation studies. Prolonged ligation of sciatic nerve expressively induced hyperalgesia as well as allodynia in rats. KB 09 and KB 10 substantially attenuated the CCI elicited hyperalgesia and allodynia. They significantly reduced the biomarkers of pain and inflammation like Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ELISA and while enhanced the GSH, SOD and CAT and diminished the MDA levels during antioxidant assays. KB 09 displayed -9.62 kcal/mol with TNF-α and -7.68 kcal/mol binding energy with IL-6 whereas KB 10 exhibited binding energy of -8.20 kcal/mol with IL-6 while -11.68 kcal/mol with TNF-α and hence both trial compounds ensured stable interaction with IL-6 and TNF-α during computational analysis. The results advocated that both methanimine derivatives might be novel candidates for attenuation of CCI-induced neuropathic pain prospects via anti-nociceptive, anti-inflammatory and antioxidant mechanisms.
当前药物治疗所涉及的多因素病因、复杂的临床影响、基于剂量的副作用以及疼痛缓解程度，无法完全解决慢性神经性疼痛患者的问题，这使得新型药物治疗成为长期需求。因此，本研究探讨了两种新型甲亚胺类似物，即（E）-N-（4-硝基亚苄基）-4-氯-2-碘苯甲胺（KB 09）和（E）-N-（4-甲基亚苄基）-4-氯-2-碘苯甲胺（KB 10）对大鼠坐骨神经慢性缩窄损伤（CCI）诱导的神经性疼痛的改善能力。在第0、3、7、14和21天等不同实验时间点，进行了动态和静态痛觉过敏、冷、热和机械性痛觉过敏以及转棒活动等标准行为测试。对脊髓组织进行了酶联免疫吸附测定（ELISA），并对坐骨神经进行了抗氧化测定，同时进行了分子对接和模拟研究。坐骨神经的长期结扎显著诱导了大鼠的痛觉过敏和异常性疼痛。KB 09和KB 10显著减轻了CCI诱导的痛觉过敏和异常性疼痛。它们在ELISA中显著降低了白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）等疼痛和炎症生物标志物，而在抗氧化测定中提高了谷胱甘肽（GSH）、超氧化物歧化酶（SOD）和过氧化氢酶（CAT）水平，并降低了丙二醛（MDA）水平。KB 09与TNF-α的结合能为-9.62 kcal/mol，与IL-6的结合能为-7.68 kcal/mol，而KB 10与IL-6的结合能为-8.20 kcal/mol，与TNF-α的结合能为-11.68 kcal/mol，因此在计算分析中，两种受试化合物都确保了与IL-6和TNF-α的稳定相互作用。结果表明，这两种甲亚胺衍生物可能是通过抗伤害感受、抗炎和抗氧化机制减轻CCI诱导的神经性疼痛的新型候选药物。
