The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA.
Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA.
Neuropharmacology. 2018 May 1;133:415-428. doi: 10.1016/j.neuropharm.2018.02.024. Epub 2018 Feb 24.
Adiponectin is an important adipocyte-derived plasma protein that has beneficial effects on cardio- and cerebrovascular diseases. A low level of plasma Adiponectin is associated with increased mortality post ischemic stroke; however, little is known about the causal role of Adiponectin as well as its molecular mechanisms in neonatal hypoxia ischemia (HI). In the present study, ten-day-old rat pups were subjected to right common carotid artery ligation followed by 2.5 h hypoxia. Recombinant human Adiponectin (rh-Adiponectin) was administered intranasally 1 h post HI. Adiponectin Receptor 1 (AdipoR1) siRNA, APPL1 siRNA, LKB1 siRNA were administered through intracerebroventricular injection 48 h before HI. Brain infarct area measurement, neurological function test, western blot, Fluoro Jade C (FJC), TUNEL, and immunofluorescence staining were conducted. Results revealed that endogenous Adiponectin, AdipoR1 and APPL1 were increased in a time dependent manner after HI. Administration of rh-Adiponectin reduced brain infarct area, neuronal apoptosis, brain atrophy and improved neurological function at 24 h and 4 weeks post HI. Furthermore, rh-Adiponectin treatment increased Adiponectin, AdipoR1, APPL1, cytosolic LKB1, p-AMPK expression levels and thereby attenuated apoptosis as shown by the decreased expression of the pro-apoptotic marker, Cleaved Caspase 3 (C-Cas3), as well as the number of FJC and TUNEL positively stained neurons. AdipoR1, APPL1 and LKB1 siRNAs abolished the anti-apoptotic effects of rh-Adiponectin at 24 h after HI. Collectively, the data provided evidence that intranasal administration of rh-Adiponectin attenuated neuronal apoptosis at least in part via activating AdipoR1/APPL1/LKB1/AMPK signaling pathway. Adiponectin could represent a therapeutic target for treatment of neonatal hypoxic ischemic encephalopathy.
脂联素是一种重要的脂肪细胞来源的血浆蛋白，对心血管和脑血管疾病有有益影响。血浆脂联素水平低与缺血性中风后死亡率增加有关；然而，脂联素在新生儿缺氧缺血（HI）中的因果作用及其分子机制知之甚少。在本研究中，10 天大的大鼠幼仔接受右颈总动脉结扎，随后进行 2.5 小时缺氧。HI 后 1 小时通过鼻内给予重组人脂联素（rh-Adiponectin）。AdipoR1 siRNA、APPL1 siRNA、LKB1 siRNA 通过侧脑室注射在 HI 前 48 小时给予。进行脑梗死面积测量、神经功能测试、western blot、Fluoro Jade C（FJC）、TUNEL 和免疫荧光染色。结果表明，HI 后，内源性脂联素、AdipoR1 和 APPL1 呈时间依赖性增加。rh-Adiponectin 给药可减少 HI 后 24 小时和 4 周时的脑梗死面积、神经元凋亡、脑萎缩并改善神经功能。此外，rh-Adiponectin 处理增加了脂联素、AdipoR1、APPL1、细胞质 LKB1、p-AMPK 的表达水平，从而减少了促凋亡标志物Cleaved Caspase 3（C-Cas3）的表达，以及 FJC 和 TUNEL 阳性染色神经元的数量。AdipoR1、APPL1 和 LKB1 siRNA 在 HI 后 24 小时消除了 rh-Adiponectin 的抗凋亡作用。总之，这些数据提供了证据，表明鼻内给予 rh-Adiponectin 通过激活 AdipoR1/APPL1/LKB1/AMPK 信号通路至少部分减轻了神经元凋亡。脂联素可能成为治疗新生儿缺氧缺血性脑病的治疗靶点。
