Combination of Peroxisome Proliferator-activated Receptor Gamma (PPARγ) Agonist and PPAR Gamma Co-Activator 1α (PGC-1α) Activator Ameliorates Cognitive Deficits, Oxidative Stress, and Inflammation in Rodent Model of Parkinson’s Disease

Abstract

Background: PPAR gamma co-activator 1α (PGC-1α) is known as the master regulator of mitochondrial biogenesis. It is also a co-activator of peroxisome proliferator-activated receptor-gamma (PPARγ) and plays a role in preventing mitochondrial dysfunction in several neurodegenerative disorders, including Parkinson’s disease (PD). Depletion in the levels of these proteins has been linked to oxidative stress, inflammation, and DNA damage, all of which are known to contribute to the pathogenesis of PD. Objective: In the present study, combination therapy of PPARγ agonist (GW1929) and PGC-1α activator (alpha-lipoic acid) was employed to ameliorate cognitive deficits, oxidative stress, and inflammation associated with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Results: Our study showed that MPTP-induced PD rats exhibited an increase in oxidative stress and inflammation, leading to cognitive deficits. Furthermore, MPTP-induced PD rats also exhibited reduced mitochondrial biogenesis in comparison to control and sham animals. Intraperitoneal administration of GW 1929 and alpha-lipoic acid in doses lower than those earlier reported individually in literature led to an improvement in the cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and inflammation. In addition, an increase in mitochondrial biogenesis was also observed after the combination of these pharmacological agents. Conclusion: Our results provide a rationale for the development of agents targeting PPARγ and PGC-1α as potent therapeutics for the treatment of neurological diseases like PD.

Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinson’s disease

“…10 C). PGC-1α and PGC-1ß serve pivotal functions in metabolic control (Handschin & Spiegelman 2006) and, importantly, have been implicated in dopamine neuron survival (Jiang et al , 2016) and the pathogenesis of PD (Zheng et al , 2010; Su et al , 2015; Piccinin et al , 2021; Das et al, 2021; Jamwal et al , 2021). Similar roles have been ascribed to PPAR-α (Gottschalk et al , 2021; Avagliano et al , 2016), PEA’s primary receptor and obligatory PGC-1α partner (Handschin & Spiegelman 2006).…”

Dysmetabolism and Neurodegeneration: Trick or Treat?

“…Promising results from preclinical studies reported that pioglitazone and rosiglitazone are able to ameliorate memory and cognitive impairment and decrease AD-related pathology in several rodent models of AD, including the 3xTg-AD mice and Tg2576 mice, by enhancing AKT signaling and attenuating tau hyperphosphorylation, neuroinflammation, and AD pathology [ 254 , 255 , 256 , 257 ]. Furthermore, pioglitazone, rosiglitazone and mitoglitazone were also shown to prevent dopaminergic neurodegeneration and locomotor deficits in MPTP-, STZ-, and 6-OHDA-lesioned rodent models of PD, by modulating the neuroinflammatory response in a neuroprotective fashion [ 258 , 259 , 260 , 261 , 262 , 263 , 264 ]. These findings are consistent with data from clinical studies.…”

Neuroprotective Potential of HC070, a Potent TRPC5 Channel Inhibitor in Parkinson′s Disease Models: A Behavioral and Mechanistic Study

“…Calculations were performed using the 2 −ΔΔCT method, and results were expressed as fold change relative to the sham group. 5 3.10. Isolation of the Mitochondria.…”

“…2−4 Various preclinical studies have previously targeted these pathophysiological alterations but with limited clinical success. 5,6 Therefore, there is always a need to look for newer approaches for PD treatment.…”