Bazaz Mohd Rabi, Padhy Hara Prasad, Dandekar Manoj P
Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India.
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, Balanagar, Hyderabad, 500037, Telangana, India.
Metab Brain Dis. 2025 Jan 3;40(1):81. doi: 10.1007/s11011-024-01517-2.
The negative impact of repeated-mild traumatic brain injury (rmTBI) is profoundly seen in circadian-disrupted individuals. The unrelenting inflammation, glial activation, and gut dysbiosis are key neuropathological aberrations in the aftermath of rmTBI. In this study, we examined the impact of chitosan lactate (CL) on circadian disturbance (CD) + rmTBI-generated neurological dysfunctions and its prebiotic response on the gut-brain axis. Adult C57BL/6 mice were exposed to circadian disruption (CD) prior to rmTBI insults. The neurobehavioral changes were assessed by rotarod, open-field test (OFT), elevated zero maze (EZM), forced-swim test (FST), Y-maze, and novel object recognition test (NORT). The inflammatory, neuronal, and synaptic markers in the frontal cortex and hippocampus, and cecal gut microbiota phylum were examined using RT-PCR and western blotting. The goblet cells, tight junction proteins (occludin and zona occludens-1), and short-chain fatty acids (SCFAs) were analyzed using immunohistochemistry, alcian-blue PAS staining, and H-NMR methods. Mice exposed to CD + rmTBI (CDR) displayed robust neurological dysfunctions in rotarod, anxiety- and depressive-like behavior in EZM and FST, and cognition deficits in Y-maze and NORT. Administration of CL (1 and 3 mg/kg) mitigated the above neurobehavioral abnormalities. CL treatment also normalized the levels of inflammatory markers (NF-κB, IL-6, IL-18, and TNF-α), brain-derived neurotrophic factor, and neuronal/synaptic proteins (doublecortin, synaptophysin, and postsynaptic density protein-95). Increased goblet cells and tight junction proteins in the colon and SCFAs in the cecal samples indicated improved gut integrity following CL treatment. The results indicate that CL mitigated CDR-inflicted neurological abnormalities in mice by modulating neuroinflammation and gut-brain interactions.
在昼夜节律紊乱的个体中，反复轻度创伤性脑损伤（rmTBI）的负面影响极为明显。持续的炎症、胶质细胞激活和肠道微生物失调是rmTBI后关键的神经病理学异常。在本研究中，我们研究了乳酸壳聚糖（CL）对昼夜节律紊乱（CD）+rmTBI引起的神经功能障碍的影响及其对肠-脑轴的益生元反应。成年C57BL/6小鼠在遭受rmTBI损伤之前先经历昼夜节律紊乱（CD）。通过转棒试验、旷场试验（OFT）、高架零迷宫（EZM）、强迫游泳试验（FST）、Y迷宫试验和新物体识别试验（NORT）评估神经行为变化。使用RT-PCR和蛋白质印迹法检测额叶皮质和海马中的炎症、神经元和突触标记物，以及盲肠肠道微生物菌群。使用免疫组织化学、阿尔辛蓝PAS染色和H-NMR方法分析杯状细胞、紧密连接蛋白（闭合蛋白和封闭小带蛋白-1）和短链脂肪酸（SCFAs）。暴露于CD+rmTBI（CDR）的小鼠在转棒试验中表现出严重的神经功能障碍，在EZM和FST中表现出焦虑样和抑郁样行为，在Y迷宫试验和NORT中表现出认知缺陷。给予CL（1和3mg/kg）可减轻上述神经行为异常。CL治疗还使炎症标记物（NF-κB、IL-6、IL-18和TNF-α）、脑源性神经营养因子以及神经元/突触蛋白（双皮质素、突触素和突触后密度蛋白-95）的水平恢复正常。结肠中杯状细胞和紧密连接蛋白增加，盲肠样本中的SCFAs增加，表明CL治疗后肠道完整性得到改善。结果表明，CL通过调节神经炎症和肠-脑相互作用减轻了CDR对小鼠造成的神经异常。
