Chronic oleoylethanolamide treatment attenuates diabetes-induced mice encephalopathy by triggering peroxisome proliferator-activated receptor alpha in the hippocampus
Chronic oleoylethanolamide treatment attenuates diabetes-induced mice encephalopathy by triggering peroxisome proliferator-activated receptor alpha in the hippocampus
复制标题
长期油酰乙醇酰胺治疗通过触发海马中的过氧化物酶体增殖物激活受体α来减轻糖尿病引起的小鼠脑病
DOI：
10.1016/j.neuint.2019.104501
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发表时间：
2019-10-01
影响因子：
4.2
通讯作者：
Yang, Lichao
中科院分区：
文献类型：
--
作者：
Ren, Tong;Liu, Jinfeng;Yang, Lichao
脑是糖尿病终末器官损害的部位。糖尿病相关的认知功能障碍（Diabetes-associated cognitive dysfunction，DM），又称糖尿病脑病（diabeticencephalopathy，DE），是指2型糖尿病患者认知功能下降，尤其是情景记忆、认知能力和精神状态下降，最终导致阿尔茨海默病（Alzheimer's disease，AD）。目前的证据支持异常突触、能量代谢失衡、晚期糖基化终产物（AGEs）积累和Tau蛋白过度磷酸化与糖尿病引起的认知功能障碍有关。油酰乙醇胺（OEA）是一种内源性过氧化物酶体增殖物激活受体α（PPAR α）激动剂，具有抗高脂血症、抗炎和神经保护作用。然而，OEA对DE的影响尚不清楚。因此，我们使用Morris水迷宫（MWM）测试其对高脂饮食和链脲佐菌素（HFD + STZ）诱导的糖尿病C57 BL/6 J和PPAR α（-/-）小鼠的认知功能障碍的影响。通过海马区神经元染色、痴呆标志物和神经可塑性等指标评价海马区神经病理学改变。结果表明，慢性OEA治疗显著降低糖尿病小鼠的高血糖，恢复认知能力，减少痴呆标志物，并抑制海马神经元丢失和神经可塑性损伤。相比之下，通过OEA施用在PPARa敲除小鼠中未观察到MWM性能和神经元损失的变化。这些结果表明，OEA可能通过激活PPARa信号通路为DE提供潜在的替代治疗。
Brain is a site of diabetic end-organ damage. Diabetes-associated cognitive dysfunction, referred as "diabetic encephalopathy" (DE) has been coined for the patients with type 2 diabetes mellitus showing decline in their cognitive function, especially weak episodic memory, cognitive inflexibility and poor psychomotor performance leading towards Alzheimer's disease. Current evidence supported that aberrant synapses, energy metabolism imbalance, advanced glycation end products (AGEs) accumulation and Tau hyperphosphorylation are associated with cognition deficits induced by diabetes. Oleoylethanolamide (OEA), an endogenous peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, has anti-hyperlipidemia, anti-inflammatory and neuroprotective activities. However, the effect of OEA on DE is unknown. Therefore, we tested its influence against cognitive dysfunction in high fat diet and streptozotocin (HFD + STZ)-induced diabetic C57BL/6J and PPAR alpha(-/-) mice using Morris water maze (MWM) test. Neuron staining, dementia markers and neuroplasticity in the hippo campus were assessed to evaluate the neuropathological changes. The results showed that chronic OEA treatment significantly lowered hyperglycemia, recovered cognitive performance, reduced dementia markers, and inhibited hippocampal neuron loss and neuroplasticity impairments in diabetic mice. In contrast, the changes in MWM performance and neuron loss were not observed in PPARa knockout mice via OEA administration. These results indicated that OEA may provide a potential alternative therapeutic for DE by activating PPARa signaling.