Department of Physiology, Hamdard Institute of Medical Sciences & Research, Jamia Hamdard (Deemed University), New Delhi, India.
Department of Physiology, Hamdard Institute of Medical Sciences & Research, Jamia Hamdard (Deemed University), New Delhi, India.
Eur J Pharmacol. 2022 Aug 5;928:175095. doi: 10.1016/j.ejphar.2022.175095. Epub 2022 Jun 18.
Snake envenomation leads to the formation of damage-associated molecular patterns (DAMPs), which are mediated by endogenous intracellular molecules. These are recognized by pattern-recognition receptors (PRRs) and can induce sterile inflammation.
In the present study, we aim at understanding the mechanisms involved in DAMPs induced sterile inflammation to unravel the novel therapeutic strategies for treating snake bites. The potential of benzodiazepinone derivatives to act against snake venom induced inflammation has been explored in the present investigation.
Three compounds VA 17, VA 43 and PA 03 were taken from our library of synthetic compounds. Oxidative stress markers such as lipid peroxidation, superoxide and nitric oxide were measured along with the analysis of DAMPs (IL6, HMGB1, vWF, S100b and HSP70). These compounds have been docked using molecular docking against the snake venom PLA structure (PDB code: 1OXL).
The compounds have been found to effectively neutralize viper and cobra venoms induced lethal activity both ex vivo and in vivo. The compounds have also neutralized the viper venom induced hemorrhagic, coagulant, anticoagulant reactions as well as inflammation. The fold of protection have always been found to be higher in case of ex vivo than in in vivo. These compounds have neutralized the venom induced DAMPs as exhibited by IL6, HMGB1, vWF, S100b and HSP70. The fold of neutralization is found to be higher in VA 43.
The identified compounds could be used as potential candidates for developing treatment of snakebites in areas where antiserums are not yet available.
蛇毒会导致损伤相关分子模式（DAMPs）的形成，这些模式是由内源性细胞内分子介导的。这些被模式识别受体（PRRs）识别，并能引起无菌性炎症。
本研究旨在了解 DAMPs 诱导的无菌性炎症的机制，以揭示治疗蛇咬伤的新治疗策略。本研究探讨了苯并二氮卓酮衍生物对抗蛇毒诱导炎症的潜力。
从我们的合成化合物库中选取了三种化合物 VA 17、VA 43 和 PA 03。测定了氧化应激标志物，如脂质过氧化、超氧化物和一氧化氮，以及 DAMPs（IL6、HMGB1、vWF、S100b 和 HSP70）的分析。这些化合物已经通过分子对接与蛇毒 PLA 结构（PDB 代码：1OXL）进行了对接。
这些化合物在体外和体内均能有效地中和蝰蛇和眼镜蛇毒液引起的致死活性。这些化合物还中和了蝰蛇毒液引起的出血、凝血、抗凝反应以及炎症。在体外，保护倍数总是高于体内。这些化合物中和了毒液诱导的 DAMPs，如 IL6、HMGB1、vWF、S100b 和 HSP70。VA 43 的中和倍数较高。
已鉴定的化合物可作为在尚无抗血清的地区开发治疗蛇咬伤的潜在候选药物。
