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Neuroprotective effects of a novel antidiabetic drug (D-Ser2)Oxm on amyloid β rotein-induced cytotoxicity

HAN Yu-Fei, HOLSCHER Christian, , WANG Zhao-Jun, , ZHANG Jun, YUAN Li, TONG Jia-Qing, WANG Dan-Dan, , WU Mei-Na, QI Jin-Shun^*

1Department of Physiology, Key Laboratory for Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan 030001, China； 2Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, UK

Abstract

The accumulation and neurotoxicity of amyloid β protein (Aβ) in the brain is one of major pathological hallmarks of Alzheimer's disease (AD). The effective drugs against Aβ have been still deficient up to now. According to a most recent study, (D-Ser2)Oxm, a new antidiabetic drug, not only improves the disorders in plasma glucose and insulin in type 2 diabetes mellitus (T2DM) rats, but also exerts positive effects on hippocampal neurogenesis and synaptogenesis. However, it is still unclear whether (D-Ser2)Oxm can directly protect cultured neurons against Aβ1-42-induced cytotoxicity. In the present study, we investigated the neuroprotective
effects of (D-Ser2)Oxm on the cultured primary hippocampal neurons by testing the cell viability, neuronal apoptosis, mitochondrial membrane potential and intracellular calcium concentration. The results showed that treatment with (D-Ser2)Oxm effectively reversed Aβ1-42-induced decline in cell viability (P < 0.001), and this protective effect could be inhibited by the pretreatment with exendin(9-39), a GLP-1 receptor blocker. (D-Ser2)Oxm treatment also decreased Aβ1-42-induced neuronal early apoptosis and down-regulated apoptotic protein caspase3. Meantime, (D-Ser2)Oxm treatment inhibited Aβ1-42-induced [Ca2+]i elevation, mitochondrial membrane potential depolarization, and glycogen synthase kinase-3β (GSK3β) activation. These results suggest that (D-Ser2)Oxm can protect hippocampal neurons against Aβ1-42-induced cytotoxicity and this effect may be related to activation of GLP-1 receptors, regulation of intracellular calcium homeostasis and stabilization of mitochondrial membrane potential.

Key words: (D-Ser2)Oxm; amyloid β protein; cellular apoptosis; caspase3; intracellular calcium imaging; mitochondrial membrane potential; GSK3β; hippocampal neuron

Received: 2015-12-03　　Accepted: 2016-03-31

Corresponding author: 祁金顺　　E-mail: jinshunqi2009@163.com

Citing This Article：

HAN Yu-Fei, HOLSCHER Christian, , WANG Zhao-Jun, , ZHANG Jun, YUAN Li, TONG Jia-Qing, WANG Dan-Dan, , WU Mei-Na, QI Jin-Shun. Neuroprotective effects of a novel antidiabetic drug (D-Ser2)Oxm on amyloid β rotein-induced cytotoxicity. Acta Physiol Sin 2016; 68 (3): 265-275 (in Chinese with English abstract).