Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, 500037, India.
Department of Medical Devices, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, 500037, India.
Eur J Pharmacol. 2024 Apr 15;969:176436. doi: 10.1016/j.ejphar.2024.176436. Epub 2024 Feb 27.
The severity of inevitable neurological deficits and long-term psychiatric disorders in the aftermath of traumatic brain injury is influenced by pre-injury biological factors. Herein, we investigated the therapeutic effect of chitosan lactate on neurological and psychiatric aberrations inflicted by circadian disruption (CD) and controlled-cortical impact (CCI) injury in mice. Firstly, CD was developed in mice by altering sporadic day-night cycles for 2 weeks. Then, CCI surgery was performed using a stereotaxic ImpactOne device. Mice subjected to CCI displayed a significant disruption of motor coordination at 1-, 3- and 5-days post-injury (DPI) in the rotarod test. These animals showed anxiety- and depression-like behaviors in the elevated plus maze and forced-swim test at 14 and 15 DPI, respectively. Notably, mice subjected to CD + CCI exhibited severe cognitive impairment in Y-maze and novel object recognition tasks. The compromised neurological, psychiatric, and cognitive functions were mitigated in chitosan-treated mice (1 and 3 mg/mL). Immunohistochemistry and real-time PCR assay results revealed the magnified responses of prima facie biomarkers like glial-fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 in the pericontusional brain region of the CD + CCI group, indicating aggravated inflammation. We also noted the depleted levels of brain-derived neurotrophic factor and augmented expression of toll-like receptor 4 (TLR4)-leucine-rich-containing family pyrin domain-containing 3 (NLRP3) signaling [apoptosis-associated-speck-like protein (ASC), caspase-1, and interleukin 1-β] in the pericontusional area of CD + CCI group. CCI-induced changes in the astrocyte-glia and aggravated immune responses were ameliorated in chitosan-treated mice. These results suggest that the neuroprotective effect of chitosan in CCI-induced brain injury may be mediated by inhibition of the TLR4-NLRP3 axis.
创伤性脑损伤后不可避免的神经功能缺损和长期精神障碍的严重程度受损伤前生物因素的影响。在此，我们研究了壳聚糖乳酸盐对昼夜节律紊乱（CD）和皮质控制冲击（CCI）损伤诱导的小鼠神经和精神异常的治疗作用。首先，通过改变 2 周的散发性日夜周期，在小鼠中建立 CD。然后，使用立体定向 ImpactOne 设备进行 CCI 手术。CCI 手术后，小鼠在旋转棒试验中于 1、3 和 5 天（DPI）表现出运动协调的显著中断。这些动物在高架十字迷宫和强迫游泳试验中分别于 14 和 15 DPI 显示出焦虑和抑郁样行为。值得注意的是，经历 CD+CCI 的小鼠在 Y 迷宫和新物体识别任务中表现出严重的认知障碍。在壳聚糖处理的小鼠中，神经、精神和认知功能受损得到缓解（1 和 3 mg/mL）。免疫组织化学和实时 PCR 分析结果显示，在 CD+CCI 组的损伤周围脑区，初步生物标志物如胶质纤维酸性蛋白和钙结合衔接蛋白 1 的反应放大，表明炎症加重。我们还注意到，在 CD+CCI 组损伤周围区域，脑源性神经营养因子水平降低，Toll 样受体 4（TLR4）-富含亮氨酸重复家族吡喃结构域包含 3（NLRP3）信号[凋亡相关斑点样蛋白（ASC）、半胱天冬酶-1 和白细胞介素 1-β]表达增加。CCI 诱导的星形胶质细胞-神经胶质变化和加重的免疫反应在壳聚糖处理的小鼠中得到改善。这些结果表明，壳聚糖在 CCI 诱导的脑损伤中的神经保护作用可能是通过抑制 TLR4-NLRP3 轴介导的。
