Glitazones, PPAR-γ and Neuroprotection

Abstract

: The transcriptional factor PPAR-γ belongs to the nuclear receptor family, which has become a potential therapeutic target for several neurodegenerative diseases and metabolic disorders. Interestingly, PPAR-γ has been reported to have beneficial effects in various chronic neurological conditions via upregulation of its transcriptional co-activator PGC-1α and followed by regulation of multiple molecular events. Although several factors contribute to the progression of neurodegeneration, the dysfunction of PGC-1α expression is primarily interlinked with the pathogenesis of major neurodegenerative diseases. This review gives an insight that ligand-dependent activation of PPAR-γ by glitazones could initiate the structural conformational changes of the secondary proteins, thus recruiting the PGC-1α to form a regulatory stable complex which hampers the various molecular pathways contributing to neurodegeneration. The promising outcomes of the preliminary in silico studies included in this review support that PPAR-γ dependent activation of central PGC-1α signaling by novel glitazones is an encouraging strategy to enhance the oxy-radicals detoxifying system, anti-inflammatory responses, and mitochondrial biogenesis required for neuroprotection in various neurodegenerative conditions.

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 ].…”

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

“… 111 Pioglitazone might reduce the risk of dementia by 47% in populations with diabetes. 48 Pioglitazone and glitazones can activate peroxisome proliferator-activated receptor-γ (PPAR-γ), 118 which can improve cell adhesion factors and inflammatory factors in brain cells. This receptor can also act on other tissues and regulate glucose metabolism and overall energy homeostasis.…”

PPAR-γ Activation Alleviates Osteoarthritis through Both the Nrf2/NLRP3 and PGC-1α/Δψm Pathways by Inhibiting Pyroptosis

“…PPAR- γ activated by Piog suppressed diabetes-induced atrial mitochondrial oxidative stress and protected mitochondrial biogenesis and Δψ m , which was blunted by PGC-1 α siRNA transfection [ 29 ]. The PPAR- γ -dependent activation of PGC-1 α signaling by glitazones is a plausible strategy to elevate antioxidative and anti-inflammatory responses as well as mitochondrial biogenesis for neuroprotection in various neurological conditions [ 27 , 56 ]. Thiazolidinediones, including rosiglitazone and Piog, binding to GPR40 induced p38 MAPK phosphorylation and subsequently activated PGC-1 α independent of PPAR- γ activation in the human endothelium.…”