Chitkara College of Pharmacy, Chitkara University, Changdigarh 140401, Punjab, India.
Department of Vegetable Crops and Medicinal Plants, University of Life Sciences in Lublin, 50A Doświadczalna Street, 20-280 Lublin, Poland.
Molecules. 2021 Nov 9;26(22):6773. doi: 10.3390/molecules26226773.
Chondroitin sulfate is a proteoglycan component of the extracellular matrix (ECM) that supports neuronal and non-neuronal cell activity, provides a negative domain to the extracellular matrix, regulates the intracellular positive ion concentration, and maintains the hypersynchronous epileptiform activity. Therefore, the present study hypothesized an antiepileptic potential of chondroitin sulfate (CS) in pentylenetetrazole-induced kindled epilepsy and pilocarpine-induced status epilepticus in mice. Levels of various oxidative stress markers and inflammatory mediators were estimated in the brain tissue homogenate of mice, and histopathological changes were evaluated. Treatment with valproate (110 mg/kg; i.p.) as a standard drug and chondroitin sulfate (100 & 200 mg/kg, p.o.) significantly ( < 0.01) and dose-dependently prevented the severity of kindled and spontaneous recurrent seizures in mice. Additionally, chondroitin sulfate showed its antioxidant potential by restoring the various biochemical levels and anti-inflammatory properties by reducing NF-kB levels and pro-inflammatory mediators like TNF-alpha, IL-1β, and IL-6, indicating the neuroprotective effect as well as the suppressed levels of caspase-3, which indicated a neuroprotective treatment strategy in epilepsy. The proteoglycan chondroitin sulfate restores the normal physiology and configuration of the neuronal tissue. Further, the molecular docking of chondroitin sulfate at the active pockets of TNF-alpha, IL-1β, and IL-6 showed excellent interactions with critical amino acid residues. In conclusion, the present work provides preclinical evidence of chondroitin sulfate as a new therapeutic approach in attenuating and preventing seizures with a better understanding of the mechanism of alteration in ECM changes influencing abnormal neuronal activities.
硫酸软骨素是细胞外基质（ECM）的蛋白聚糖成分，支持神经元和非神经元细胞的活动，为细胞外基质提供负电荷区域，调节细胞内正离子浓度，并维持超同步癫痫样活动。因此，本研究假设硫酸软骨素（CS）在戊四氮诱导的点燃性癫痫和匹罗卡品诱导的癫痫持续状态中具有抗癫痫作用。在小鼠脑组织匀浆中估计了各种氧化应激标志物和炎症介质的水平，并评估了组织病理学变化。用丙戊酸钠（110mg/kg；腹腔注射）作为标准药物和硫酸软骨素（100 和 200mg/kg，口服）进行治疗，显著（<0.01）并呈剂量依赖性地预防了小鼠点燃性和自发性复发性癫痫发作的严重程度。此外，硫酸软骨素通过恢复各种生化水平和通过降低 NF-kB 水平和促炎介质如 TNF-α、IL-1β 和 IL-6 来发挥其抗氧化潜力，表明其具有神经保护作用以及抑制 caspase-3 的水平，这表明在癫痫中具有神经保护治疗策略。蛋白聚糖硫酸软骨素恢复了神经元组织的正常生理和结构。此外，硫酸软骨素在 TNF-α、IL-1β 和 IL-6 的活性口袋中的分子对接显示出与关键氨基酸残基的优异相互作用。总之，本工作提供了硫酸软骨素作为减轻和预防癫痫发作的新治疗方法的临床前证据，并更好地了解 ECM 变化影响异常神经元活动的机制。
