Glitazones Activate PGC-1α Signaling via PPAR-γ: A Promising Strategy for Antiparkinsonism Therapeutics

Abstract

Understanding various aspects of Parkinson's disease (PD) by researchers could lead to a better understanding of the disease and provide treatment alternatives that could significantly improve the quality of life of patients suffering from neurodegenerative disorders. Significant progress has been made in recent years toward this goal, but there is yet no available treatment with confirmed neuroprotective effects.Recent studies have shown the potential of PPARγ agonists, which are the ligand activated transcriptional factor of the nuclear hormone superfamily, as therapeutic targets for various neurodegenerative disorders. The activation of central PGC-1α mediates the potential role against neurogenerative diseases like PD, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Further understanding the mechanism of neurodegeneration and the role of glitazones in the activation of PGC-1α signaling could lead to a novel therapeutic interventions against PD. Keeping this aspect in focus, the present review highlights the pathogenic mechanism of PD and the role of glitazones in the activation of PGC-1α via PPARγ for the treatment of neurodegenerative disorders.

Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson’s Disease

“…Rather than a general increase in activity, another interpretation is that GBA1 in mutant flies could have a clock-dependent effect and alter evening and morning anticipatory activity ( Figure 3 C,D). While our results corroborate previous studies in other model organisms for the effective use of glitazones as neuroprotective agents [ 23 , 24 , 25 , 26 , 27 ], the present study only considered glitazone treatment by feeding flies throughout their development and testing post-eclosion. Fly dGBA1b is ubiquitously expressed in both the larval and adult brain [ 13 , 14 ]; therefore, our study design supports an effect of glitazone treatment that is dependent on development.…”

“…Thiazolidinediones (TZDs) include pioglitazone, troglitazone, and rosiglitazone [ 19 , 20 , 21 , 22 ]. Several studies have shown that pioglitazone and rosiglitazone exert neuroprotective and anti-inflammatory effects in models of PD; it is believed that these effects are exerted through peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) activation [ 23 , 24 , 25 , 26 , 27 ]. Administration of pioglitazone in an MPTP rhesus monkey model of PD showed a reduction in dopaminergic neurodegeneration and the infiltration of CD68-positive macrophages in the nigrostriatal area [ 28 ].…”

Prospects of antidiabetic drugs in the treatment of neurodegenerative disease

“…[90] Pioglitazone and rosiglitazone exert neuroprotective effects in a series of animal models of PD and AD, significantly improving behavior and motor responses. [91][92][93][94] TZD and rosiglitazone improve motor deterioration and mutant Htt aggregation in the R6/2 and N171-82Q mouse models of HD. [95][96][97][98] Pioglitazone delays the onset of ALS and significantly enhances the survival time of superoxide dismutase (SOD1)-G93A transgenic ALS mouse model.…”

The Potential Role of PPARs in the Fetal Origins of Adult Disease

“…An oral dose of pioglitazone (PPARγ agonist) effectively increases the expression of antioxidants and blocks neuroinflammation [ 144 ]. Based on the findings described above, synthetic PPARγ agonists have been suggested as therapeutic medicines for the treatment of CNS diseases such as PD [ 184 ], AD [ 185 ], HD, and Autism spectrum disorder [ 186 ].…”