Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Chungnam, 31116, Republic of Korea.
Department of Physical Therapy, College of Health Science, Youngsan University, Yangsan, Gyeongnam, 50510, Republic of Korea.
Neurochem Res. 2021 Nov;46(11):2852-2866. doi: 10.1007/s11064-021-03362-6. Epub 2021 May 29.
Transient ischemia in the brain causes blood-brain barrier (BBB) breakdown and dysfunction, which is related to ischemia-induced neuronal damage. Leakage of plasma proteins following transient ischemia is one of the indicators that is used to determine the extent of BBB dysfunction. In this study, neuronal damage/death, leakage of albumin and IgG, microgliosis, and inflammatory cytokine expression were examined in the hippocampal CA1 region, which is vulnerable to transient ischemia, following 5-min (mild) and 15-min (severe) ischemia in gerbils induced by transient common carotid arteries occlusion (tCCAo). tCCAo-induced neuronal damage/death occurred earlier and was more severe after 15-min tCCAo vs. after 5-min tCCAo. Significant albumin and IgG leakage (albumin and IgG immunoreactivity) took 1 or 2 days to begin, and immunoreactivity was markedly increased 5 days after 5-min tCCAo. While, albumin and IgG leakage began to increase 6 h after 15-min tCCAo and remained significantly higher over time than that seen in 5-min tCCAo. IgG immunoreactivity was observed in degenerating neurons and activated microglia after tCCAo, and microglia were activated to a greater extent after 15-min tCCAo than 5-min tCCAo. In addition, following 15-min tCCAo, pro-inflammatory cytokines [tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β)] immunoreactivity was significantly higher than that seen following 5-min tCCAo, whereas immunoreactivity of anti-inflammatory cytokines (IL-4 and IL-13) was lower in 15-min than 5-min tCCAo. These results indicate that duration of tCCAo differentially affects the timing and degree of neuronal damage or loss, albumin and IgG leakage and inflammatory cytokine expression in brain tissue. In addition, more severe BBB leakage is closely related to acceleration of neuronal damage through increased microglial activation and pro-inflammatory cytokine expression in the ischemic hippocampal CA1 region.
短暂性脑缺血会导致血脑屏障（BBB）破裂和功能障碍，这与缺血诱导的神经元损伤有关。短暂性脑缺血后，血浆蛋白的渗漏是确定 BBB 功能障碍程度的指标之一。在这项研究中，通过短暂性颈总动脉闭塞（tCCAo）诱导的沙鼠短暂性脑缺血，在海马 CA1 区（对短暂性脑缺血敏感）检测神经元损伤/死亡、白蛋白和 IgG 渗漏、小胶质细胞激活和炎症细胞因子表达。与 5 分钟 tCCAo 相比，15 分钟 tCCAo 引起的神经元损伤/死亡更早且更严重。显著的白蛋白和 IgG 渗漏（白蛋白和 IgG 免疫反应性）在 1 或 2 天后开始，5 分钟 tCCAo 后 5 天免疫反应性明显增加。然而，15 分钟 tCCAo 后 6 小时开始增加白蛋白和 IgG 渗漏，并且随着时间的推移，其水平一直高于 5 分钟 tCCAo。tCCAo 后，在神经元变性和激活的小胶质细胞中观察到 IgG 免疫反应性，并且 15 分钟 tCCAo 后小胶质细胞的激活程度比 5 分钟 tCCAo 后更为严重。此外，15 分钟 tCCAo 后，促炎细胞因子（肿瘤坏死因子-α（TNF-α）和白细胞介素 1β（IL-1β））免疫反应性明显高于 5 分钟 tCCAo，而 15 分钟 tCCAo 中抗炎细胞因子（IL-4 和 IL-13）的免疫反应性低于 5 分钟 tCCAo。这些结果表明，tCCAo 的持续时间不同地影响脑组织中神经元损伤或丢失、白蛋白和 IgG 渗漏以及炎症细胞因子表达的时间和程度。此外，更严重的 BBB 渗漏通过增加缺血海马 CA1 区的小胶质细胞激活和促炎细胞因子表达与神经元损伤的加速密切相关。
