Neuroprotective Effect and Mechanism of Thiazolidinedione on Dopaminergic Neurons In Vivo and In Vitro in Parkinson’s Disease

Abstract

The aim of the present study was to gain insight into the neuroprotection effects and mechanism of thiazolidinedione pioglitazone in both in vitro and in vivo MPP+/MPTP induced PD models. In vivo experimental results showed that oral treatment of pioglitazone resulted in significant improvements in behavior symptoms damaged by MPTP and increase in the survival of TH positive neurons in the pioglitazone intervention groups. In addition, oral treatment of pioglitazone increased the expression of peroxisome proliferator-activated receptor-γ coactivator of 1α (PGC-1α) and increased the number of mitochondria, along with an observed improvement in mitochondrial ultrastructure. From in vitro studies, 2,4-thiazolidinedione resulted in increased levels of molecules regulated function of mitochondria, including PGC-1α, nuclear respiratory factor 1 (NRF1), NRF2, and mitochondria fusion 2 (Mfn2), and inhibited mitochondria fission 1 (Fis1). We show that protein levels of Bcl-2 and ERK were reduced in the MPP+-treated group compared with the control group. This effect was observed to be reversed upon treatment with 2,4-thiazolidinedione, as Bcl-2 and ERK expression levels were increased. We also observed that levels of the apoptotic protein Bax showed opposite changes compared to Bcl-2 and ERK levels. The results from this study confirm that pioglitazone/2,4-thiazolidinedione is able to activate PGC-1α and prevent damage of dopaminergic neurons and restore mitochondria ultrastructure through the regulation of mitochondria function.

Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells

“…For this reason, we have tested in a cell model of DS the effects of a thiazolinedione, namely PGZ, a PPAR-γ agonist, which stimulates PGC-1α expression. PGZ plays a neuroprotective role in dopaminergic neurons in both in vitro and in vivo PD models (Wang et al, 2017), which was associated with PGC-1α induction and the regulation of proteins involved in mitochondria function (Wang et al, 2017). We intentionally used low doses of the drugs because both metformin and PGZ are known to inhibit respiratory complex I when used at high concentrations (Brunmair et al, 2004; Ghosh et al, 2007; Garcia-Ruiz et al, 2013).…”

Chronic treatment with fluoride affects the jejunum: insights from proteomics and enteric innervation analysis

“…Mitochondrial fission is implicated in the cell death through a pathway that involves caspase activation 71 , and Mitochondrial fission 1 protein (Fis1) is considered essential for mitochondrial fission 72 . Overexpression of Fis1 caused increase of mitochondrial fragmentation, which conducted to apoptosis or triggered autophagy 73 , 74 , and neuroprotective effects are correlated with inhibition of Fis1 75 .…”

Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2) and Mitochondrial Dynamics/Mitophagy in Neurological Diseases

“…In the 6-hydroxydopamine (6-OHDA)-induced rat model of PD, the cytosolic and nuclear protein levels of Nrf2 are markedly reduced, which is accompanied by facilitated DRP1-mediated mitochondrial fission [ 85 ]. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, the expression levels of FIS1 are elevated concomitantly with the reduced levels of MFN2 and Nrf2 [ 86 ], although Mendes et al [ 87 ] have reported that MPTP transiently increases the expression of Nrf2 and parkin. Thus, it is likely that reduced Nrf2 expression/activity may be relevant for mitochondrial fragmentation and impaired mitophagy in PD ( Figure 4 and Table 2 ).…”