Department of Cadre Health Care, the Xinjiang Uygur Autonomous Region People's Hospital, Urumchi, China.
Department of Anesthesiology, the Second Affiliated Hospital of Xinjiang Medical University, Urumchi, China.
CNS Neurosci Ther. 2019 Jan;25(1):69-77. doi: 10.1111/cns.12981. Epub 2018 May 27.
Type 2 diabetes mellitus (T2DM) is a complex polygenic disease that causes hyperglycemia and accounts for 90%-95% of all diabetes mellitus cases. Hence, this study aimed to examine the effects of microRNA-219 (miR-219) on inhibition of long-term potentiation (LTP) and apoptosis of hippocampal neuronal cells in T2DM mice through the N-methyl-d-aspartate receptor (NMDAR) signaling pathway regulation.
The T2DM mouse models were established, after which LTP in vivo was recorded by means of electrical biology, and the fasting blood glucose of mice was measured. Next, the density of pyramidal neurons in each group was calculated. Additionally, the expression levels of miR-219, the NMDAR signaling pathway [NMDAR1 (NR) 1, NR2A, and NR2B), downstream target proteins [calmodulin-dependent protein kinase-II (CaMK-II) and cAMP response element binding protein (CREB)], and apoptosis-related factors [Bcl2-associated X protein (Bax), c-caspase-9 and c-caspase-3] in the hippocampal tissues were determined. Finally, immunohistochemistry was applied to detect and measure the positive expression of Bax, caspase-9, and caspase-3 proteins.
The results showed that upregulation of miR-219 increases LTP and density of pyramidal neurons in the hippocampal tissues of mice, while it decreases blood glucose of db/db mice. In addition, miR-219 upregulation also leads to decreased mRNA levels of NR1, NR2A, NR2B, CaMK-II, and CREB and protein levels of NR1, NR2A, NR2B, CaMK-II, CREB, p-CREB, Bax, c-caspase-9, and c-caspase-3. Furthermore, upregulation of miR-219 inhibits positive expression of Bax, caspase-9, and caspase-3 proteins, leading to the suppression of hippocampal neuronal cell apoptosis.
The findings from this study indicated that the upregulation of miR-219 decreases LTP inhibition and hippocampal neuronal cell apoptosis in T2DM mice by downregulating the NMDAR signaling pathway, therefore suggesting that MiR-219 might be a future therapeutic strategy for T2DM.
2 型糖尿病（T2DM）是一种复杂的多基因疾病，可导致高血糖，占所有糖尿病病例的 90%-95%。因此，本研究旨在通过 N-甲基-D-天冬氨酸受体（NMDAR）信号通路调节，探讨 microRNA-219（miR-219）对 T2DM 小鼠海马神经元细胞长期电位增强（LTP）抑制和细胞凋亡的影响。
建立 T2DM 小鼠模型，通过电生物学记录体内 LTP，测量小鼠空腹血糖。然后计算每组锥体神经元的密度。此外，还测定各组海马组织中 miR-219、NMDAR 信号通路[NMDAR1（NR）1、NR2A 和 NR2B]、下游靶蛋白[钙调蛋白依赖性蛋白激酶-II（CaMK-II）和 cAMP 反应元件结合蛋白（CREB）]和凋亡相关因子[Bcl2 相关 X 蛋白（Bax）、c-caspase-9 和 c-caspase-3]的表达水平。最后，采用免疫组织化学法检测和测量 Bax、caspase-9 和 caspase-3 蛋白的阳性表达。
结果表明，miR-219 上调增加了小鼠海马组织中的 LTP 和锥体神经元密度，同时降低了 db/db 小鼠的血糖。此外，miR-219 上调还导致 NR1、NR2A、NR2B、CaMK-II 和 CREB 的 mRNA 水平降低，NR1、NR2A、NR2B、CaMK-II、CREB、p-CREB、Bax、c-caspase-9 和 c-caspase-3 的蛋白水平降低。此外，miR-219 上调抑制了 Bax、caspase-9 和 caspase-3 蛋白的阳性表达，从而抑制了海马神经元细胞凋亡。
本研究结果表明，miR-219 通过下调 NMDAR 信号通路，降低 T2DM 小鼠的 LTP 抑制和海马神经元细胞凋亡，提示 miR-219 可能成为 T2DM 的一种潜在治疗策略。
