Rahman Ziaur, Shaikh Arbaz Sujat, Rao K Venkata, Dandekar Manoj P
Department of Biological Sciences, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, India.
J Chem Neuroanat. 2024 Mar;136:102393. doi: 10.1016/j.jchemneu.2024.102393. Epub 2024 Jan 19.
Cerebral ischemia is a life-threatening health concern that leads to severe neurological complications and fatalities worldwide. Although timely intervention with clot-removing agents curtails serious post-stroke neurological dysfunctions, no effective neuroprotective intervention is available for addressing post-recanalization neuroinflammation. Herein, for the first time we studied the effect of oxyberberine (OBB), a derivative of berberine, on transient middle cerebral artery occlusion (MCAO)-generated neurological consequences in Sprague-Dawley rats. The MCAO-operated rats exhibited significant somatosensory and sensorimotor dysfunctions in adhesive removal, foot fault, paw whisker, and rotarod assays at 1 and 3 days post-surgery. These MCAO-generated neurological deficits were prevented in OBB-treated (50 and 100 mg/kg) rats, and also coincided with a smaller infarct area (in 2,3,5-triphenyl tetrazolium chloride staining) and decreased neuronal death (in cresyl violet staining) in the ipsilateral hemisphere of these animals. The immunostaining of neuronal nuclear protein (NeuN) and glial-fibrillary acidic protein (GFAP) also echoes the neuroprotective nature of OBB. The increased expression of neuroinflammatory and blood-brain barrier tight junction proteins like toll-like receptor 4 (TLR4), TRAF-6, nuclear factor kappa B (NF-κB), pNF-κB, nNOS, ASC, and IKBα in the ipsilateral part of MCAO-operated rats were restored to normal following OBB treatment. We also observed the decline in plasma levels/mRNA transcription of TNF-α, IL-1β, NLRP3, IL-6, and matrix metalloproteinase-9 and increased expression of occludin and claudin in OBB-treated rats. These outcomes imply that OBB may prevent the MCAO-induced neurological consequences and neuroinflammation by interfering with TLR4 and NLRP3 signaling in rats.
脑缺血是一种危及生命的健康问题，在全球范围内会导致严重的神经并发症和死亡。尽管及时使用溶栓药物进行干预可减少中风后严重的神经功能障碍，但目前尚无有效的神经保护干预措施来解决再灌注后的神经炎症。在此，我们首次研究了黄连素衍生物氧化黄连素（OBB）对Sprague-Dawley大鼠短暂性大脑中动脉闭塞（MCAO）所致神经后果的影响。在MCAO手术的大鼠术后1天和3天，在去除粘连、足部失误、爪须和转棒试验中表现出明显的体感和感觉运动功能障碍。在接受OBB治疗（50和100mg/kg）的大鼠中，这些由MCAO引起的神经功能缺损得到了预防，并且这些动物同侧半球的梗死面积较小（在2,3,5-三苯基氯化四氮唑染色中），神经元死亡减少（在甲酚紫染色中）。神经元核蛋白（NeuN）和胶质纤维酸性蛋白（GFAP）的免疫染色也证实了OBB的神经保护作用。MCAO手术大鼠同侧部分中，神经炎症和血脑屏障紧密连接蛋白如Toll样受体4（TLR4）、TRAF-6、核因子κB（NF-κB）、pNF-κB、nNOS、ASC和IKBα的表达增加，经OBB治疗后恢复正常。我们还观察到，在接受OBB治疗的大鼠中，血浆中TNF-α、IL-1β、NLRP3、IL-6和基质金属蛋白酶-9的水平/mRNA转录下降，而闭合蛋白和Claudin的表达增加。这些结果表明，OBB可能通过干扰大鼠的TLR4和NLRP3信号传导来预防MCAO诱导的神经后果和神经炎症。
