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Herein, we rationally designed and developed two novel glitazones (G1 and G2) to target peroxisome proliferatoractivated receptor-gamma coactivator 1-alpha (PGC-1α) signaling through peroxisome proliferator-activated receptors (PPAR)-γ agonism as a therapeutic for Parkinson's disease (PD). The synthesized molecules were analyzed by mass spectrometry and NMR spectroscopy. The neuroprotective functionality of the synthesized molecules was assessed by a cell viability assay in lipopolysaccharide-intoxicated SHSY5Y neuroblastoma cell lines. The ability of these new glitazones to scavenge free radicals was further ascertained via a lipid peroxide assay, and pharmacokinetic properties were verified using in silico absorption, distribution, metabolism, excretion, and toxicity analyses. The molecular docking reports recognized the mode of interaction of the glitazones with PPAR-γ. The G1 and G2 exhibited a noticeable neuroprotective effect in lipopolysaccharide-intoxicated SHSY5Y neuroblastoma cells with the half-maximal inhibitory concentration value of 2.247 and 4.509 μM, respectively. Both test compounds prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced motor impairment in mice, as demonstrated by the beam walk test. Further, treating the diseased mice with G1 and G2 resulted in significant restoration of antioxidant enzymes glutathione and superoxide and reduced the intensity of lipid peroxidation inside the brain tissues. Histopathological analysis of the glitazones-treated mice brain revealed a reduced apoptotic region and a rise in the number of viable pyramidal neurons and oligodendrocytes. The study concluded that G1 and G2 showed promising results in treating PD by activating PGC-1α signaling in brain via PPAR-γ agonism. However, more extensive research is necessary for a better understanding of functional targets and signaling pathways.

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Parkinson’s disease (PD) mainly affects the dopaminergic neuronal networks of the substantia nigra, which leads to both motor and nonmotor symptoms of the disease. Based on the reports from the previous studies, 95% of the cases are presented along with olfactory dysfunction. The relevant publications from 2002 to 2021 were searched and shortlisted using PubMed and Google Scholar. In this review, we have discussed the correlation between olfactory dysfunction and PD. Olfactory damage presents earlier than the motor symptoms. Because there are no current methodologies for the early detection of PD, olfactory dysfunction can be used as a potential marker for the early detection of PD and hence paving the way for better therapeutic approaches.