Adiponectin attenuates neuronal apoptosis induced by hypoxia-ischemia via the activation of AdipoR1/APPL1/LKB1/AMPK pathway in neonatal rats.

Abstract

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.

• Authors: Ningbo Xu, Yixin Zhang, Desislava Met Doycheva, Yan Ding, Yiting Zhang, Jiping Tang, Hongbo Guo, John H Zhang
• Journal: Neuropharmacology (Neuropharmacology) Vol. 133 Pg. 415-428 (05 01 2018) ISSN: 1873-7064 [Electronic] England
• PMID: 29486166 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Adiponectin
• Appl1 protein, rat
• Fluoresceins
• Nerve Tissue Proteins
• RNA, Small Interfering
• Receptors, Adiponectin
• adiponectin receptor 1, rat
• fluoro-jade C
• Protein Kinases
• Protein Serine-Threonine Kinases
• Stk11 protein, rat
• AMP-Activated Protein Kinase Kinases
• Caspase 3

Topics

• AMP-Activated Protein Kinase Kinases
• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Adiponectin (therapeutic use)
• Animals
• Animals, Newborn
• Apoptosis (drug effects)
• Body Weight (drug effects)
• Brain Infarction (drug therapy, etiology)
• Caspase 3 (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Escape Reaction (drug effects)
• Female
• Fluoresceins (metabolism)
• Gene Expression Regulation (drug effects, genetics)
• Hypoxia-Ischemia, Brain (drug therapy, pathology)
• In Situ Nick-End Labeling
• Male
• Nerve Tissue Proteins (genetics, metabolism)
• Neurologic Examination
• Neurons (drug effects)
• Protein Kinases (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA, Small Interfering (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Adiponectin (genetics, metabolism)
• Reflex (drug effects)
• Signal Transduction (drug effects, genetics)
• Statistics, Nonparametric
• Swimming (physiology)
• Time Factors