Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Department of Central Laboratory, The Central Hospital of Tai'an, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong Province 271000, China.
Brain Res Bull. 2019 Jul;149:168-174. doi: 10.1016/j.brainresbull.2019.04.019. Epub 2019 Apr 25.
Hypoglycemia is the most common complication in the treatment of diabetes mellitus. Accumulating evidence indicated that severe hypoglycemia could induce cognitive impairment. However, the molecular mechanism of regulating this progress is largely unknown.
We established a model of insulin-induced recurrent hypoglycemia in adult male Wistar rats (n = 40). Lithium chloride was injected after hypoglycemia once a day for consecutive 30 days. The loss of cognition function was evaluated by water maze test in these hypoglycemic rats. Glial cells activation and Wnt and inflammatory cytokines IL-1β, IL-6, IL-4, IL-10, TGFβ and TNFα expression were further examined to determine the mechanism of cognitive function impairment.
Hypoglycemia could induce impairment of cognitive function in rats and administration of lithium chloride could partly attenuate cognitive impairment compared to the control (p < 0.05). Lithium chloride could significantly up-regulate Wnt signaling and reduce hypoglycemia-induced neuronal death, glial cells activation and inflammatory response in the hippocampus of rats compared to the control (p < 0.05). The efficacy of lithium chloride could be reversed by injecting canonical Wnt signaling antagonist the dickkopf homolog 1.
Lithium chloride attenuated hypoglycemia-induced cognitive function impairment in rats; and it was associated with Wnt signaling up-regulation and reduction of inflammatory response. Our results suggested that activating Wnt signaling pathways and inhibiting inflammatory response were the therapeutic potential to prevent hypoglycemia-induced neurological damage.
低血糖是糖尿病治疗中最常见的并发症。越来越多的证据表明，严重低血糖可导致认知障碍。然而，调节这一进展的分子机制在很大程度上尚不清楚。
我们建立了成年雄性 Wistar 大鼠胰岛素诱导复发性低血糖模型（n=40）。低血糖后每天一次给予氯化锂注射，连续 30 天。通过水迷宫试验评估这些低血糖大鼠的认知功能丧失情况。进一步检测神经胶质细胞激活以及 Wnt 和炎症细胞因子 IL-1β、IL-6、IL-4、IL-10、TGFβ和 TNFα的表达，以确定认知功能障碍的机制。
低血糖可导致大鼠认知功能障碍，与对照组相比，氯化锂给药可部分减轻认知障碍（p<0.05）。与对照组相比，氯化锂可显著上调 Wnt 信号通路，并减少低血糖诱导的大鼠海马神经元死亡、神经胶质细胞激活和炎症反应（p<0.05）。经典 Wnt 信号通路拮抗剂 dickkopf 同源物 1 可逆转氯化锂的疗效。
氯化锂可减轻大鼠低血糖诱导的认知功能障碍；与 Wnt 信号通路的上调和炎症反应的减少有关。我们的结果表明，激活 Wnt 信号通路和抑制炎症反应是预防低血糖引起的神经损伤的潜在治疗方法。
