Yuzhen Xu1, Qian Wang2, Zhenghua Wu3, Kaili Lu1, Xiaojuan Cheng1, Weilin Jin4, Yuwu Zhao5. 1. Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. 2. Department of Central Laboratory, The Central Hospital of Tai'an, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong Province 271000, China. 3. School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200030, China. 4. Institute of Nano Biomedicine and Engineering, Department of Instrument Science and Engineering, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200030, China. 5. Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: zhaoyuwu2005@126.com.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: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. METHODS: 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. RESULTS: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. CONCLUSION: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.