Neuroprotective effects of MHY908, a PPAR α/γ dual agonist, in a MPTP-induced Parkinson's disease model.

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are considered promising therapeutic targets in several neurodegenerative diseases. A number of PPAR agonists have been shown to have neuroprotective properties in the presence of oxidative stress, neuroinflammatory response, and apoptosis in various neurodegenerative disease. MHY908 is a novel PPAR α/γ dual agonist, which has been shown to suppress inflammatory response and attenuate insulin resistance in aged rats and db/db mice. Here, we evaluated the neuroprotective effects of MHY908 in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Pretreatment with MHY908 attenuated MPTP-induced dopaminergic neuronal loss and motor deficit. MPTP-induced glial activations were mitigated by MHY908 in the nigrostriatal pathway, and MHY908 effectively blocked 1-methyl-4-phenylpyridinium (MPP+)-induced cell death and ROS production in SH-SY5Y neuroblastoma cells. Further study revealed MHY908 inhibited MPP+-induced astroglial activation by suppressing NF-κB signaling in primary astrocytes. Taken together, the present study suggests that PPAR α/γ dual agonists be considered potentially useful preventions for PD and other neurodegenerative diseases associated with neuroinflammation.

• Authors: Yujeong Lee, Jung-Hyun Cho, Seulah Lee, Wonjong Lee, Seung-Cheol Chang, Hae Young Chung, Hyung Ryong Moon, Jaewon Lee
• Journal: Brain research (Brain Res) Vol. 1704 Pg. 47-58 (02 01 2019) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 30273550 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Neuroprotective Agents
• Peroxisome Proliferator-Activated Receptors
• Reactive Oxygen Species

Topics

• Animals
• Astrocytes (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Corpus Striatum (drug effects, pathology)
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, metabolism, pathology)
• Mice
• Neural Pathways (drug effects, pathology)
• Neuroprotective Agents (administration & dosage, therapeutic use)
• Oxidative Stress (drug effects)
• Parkinsonian Disorders (drug therapy, metabolism, pathology)
• Peroxisome Proliferator-Activated Receptors (agonists)
• Reactive Oxygen Species (metabolism)
• Substantia Nigra (drug effects, pathology)