PPAR‐gamma‐mediated neuroprotection in a chronic mouse model of Parkinson’s disease

Abstract

Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-gamma agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.

Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease: Possible role of 4-hydroxynonenal (4-HNE)

“…PPARβ/δ seems to works as sensor of oxidative stress, this phenomenon being apparent at 3 mo age in Tg mice, typically characterized by the appearance of oxidative stress, [17][18][19][20][21][22] even though in the present study this event is not correlated with cell death, as apoptotic nuclei are not detected by TUNEL analysis at this age. Therefore, it appears that in the neocortex at 3 mo age, the increased levels of PPAR β/δ and the absence of an increase of 4-HNE adducts protect this brain area from the early perturbation of the redox status.…”

“…Indeed, their involvement in neurodegenerative Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer, Parkinson, and Huntington diseases, is well recognized. [15][16][17][18][19][20][21][22] Even though PPAR β/δ is the most abundant isotype in the developing and adult central nervous system (CNS), [23][24][25] its role in neurodegenerative diseases remains unclear. We have previously demonstrated that PPAR β/δ is crucial for neuronal maturation, and that its expression affects the BDNF signaling pathway.…”

Contributions of central and systemic inflammation to the pathophysiology of Parkinson's disease

“…When pioglitazone was administered to rats that were also injected intrastriatally with LPS, the resultant LPS-induced microglial activation and dopaminergic degeneration was attenuated (Hunter et al, 2007). Recently, the neuroprotective effects of rosiglitazone have been shown in the MPTP mouse model of PD; chronic administration of the drug prevented behavioural deficits, dopaminergic neuronal loss and microglial activation in the SNpc in vivo (Schintu et al, 2009). …”

Splice Variant Biomarkers for Parkinson's Disease

“…Not surprisingly, this group of genes has been associated with PD and T2DM. The peroxisome proliferator activator receptor gamma (PPAR-γ) and PPAR-γ coactivator-1α (PGC-1α) have been studied as potential therapeutic targets in PD (Schintu, et al, 2009,St-Pierre, et al, 2006,Zheng, et al, 2010 and T2DM (Han, et al, 2008) given its involvement in inflammation and lipid signaling (Wahli and Michalik, 2012). HNF4α may also play a role in intestinal lipid metabolism, oxidative stress and inflammation, processes that are implicated in both chronic diseases (Marcil, et al, 2010).…”