Rational Design, Synthesis, and In Vitro Neuroprotective Evaluation of Novel Glitazones for PGC-1α Activation via PPAR-γ: a New Therapeutic Strategy for Neurodegenerative Disorders

Justin, Antony; Mandal, Subhankar P.; Prabitha, P.; Shanmugarajan, Dhivya; Sambandam, Yuvaraj; Kabadi, Pradeep; Sekhar, Satheesh John; Sandhya, C. H.; Wadhwani, Ashish; Selvaraj, Divakar; Bharathi, Jeyabalan Jeyaram; Priya, D. Bhanu; Kumar, B. R. Prashantha

doi:10.1007/s12640-019-00132-9

Cited by 24 publications

(21 citation statements)

References 53 publications

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“…Scoring functions were used for determining the biding affinities of the ligands with the target receptors. The designed analogues were docked toward 3CS8 (target PGC-1α bound to PPAR-gamma receptor protein) in order to ascertain their binding ability to PPAR-gamma which in turn activity PGC-1 α protein (Justin et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Novel glitazone attenuates rotenone-induced toxicity in mouse model of Parkinson’s disease

Shetty¹,

Krishna²,

Kumar³

et al. 2021

J Appl Pharm Sci

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, and there are no drugs that will directly tackle the inflammatory component of PD. In the present study, we assessed the novel glitazone for reversal of rotenone-induced toxicity in experimental mouse model. The 14 virtual glitazone compounds were subjected to molecular docking study for target protein 3CS8; among these, compound C25 and C34 have shown better binding activity. Pharmacokinetics studies were conducted for the above compounds in rat model to chose best one for further toxicity and efficacy studies. The compound C25 showed better kinetic profile when compared to C34 and better t 1/2 when compared to the standard pioglitazone. Compound C25 then tested for acute toxicity by OECD guideline 423 and evaluated for its neuroprotective activity in mouse model. The activity of the compound was assessed by the behavioral parameters on weekly intervals during the study period and estimated the antioxidant level in the brain homogenate. The compound has shown good activity dose-dependently; however, further research is required to confirm its activity and to support our hypothesis.

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Section: Discussionmentioning

confidence: 99%

Novel glitazone attenuates rotenone-induced toxicity in mouse model of Parkinson’s disease

Shetty¹,

Krishna²,

Kumar³

et al. 2021

J Appl Pharm Sci

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“…The binding of agonists to PPARγ caused a change in the conformation, which attracted transcriptional coactivators, including PGC-1α. 87 The realistic interactions of agonists to PPARγ and PGC-1α were studied which showed that TZD binds to PPARγ LBD and causes conformation changes in PGC-1α, as shown in Figure 3. This work demonstrated that lack of ligand binding to the PPAR-γ LBD, the neighboring helix structure, C-terminal helix, and PGC-1α showed no structural difference.…”

Section: Pparγ Agonism and Neuroprotection Inmentioning

confidence: 99%

Glitazones Activate PGC-1α Signaling via PPAR-γ: A Promising Strategy for Antiparkinsonism Therapeutics

Prabitha

Justin

Kumar

et al. 2021

ACS Chem. Neurosci.

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Understanding various aspects of Parkinson's disease (PD) by researchers could lead to a better understanding of the disease and provide treatment alternatives that could significantly improve the quality of life of patients suffering from neurodegenerative disorders. Significant progress has been made in recent years toward this goal, but there is yet no available treatment with confirmed neuroprotective effects.Recent studies have shown the potential of PPARγ agonists, which are the ligand activated transcriptional factor of the nuclear hormone superfamily, as therapeutic targets for various neurodegenerative disorders. The activation of central PGC-1α mediates the potential role against neurogenerative diseases like PD, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Further understanding the mechanism of neurodegeneration and the role of glitazones in the activation of PGC-1α signaling could lead to a novel therapeutic interventions against PD. Keeping this aspect in focus, the present review highlights the pathogenic mechanism of PD and the role of glitazones in the activation of PGC-1α via PPARγ for the treatment of neurodegenerative disorders.

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“…These anti-inflammatory actions were shown to be mediated through its regulatory effects on PPARγ, SIRT6, and FoxO3A [108]. In addition, PPARγ-coactivator-1α (PGC-1α) which is a co-factor for transcription was implicated in the amelioration of microglial activation and reduced expression of amyloid precursor protein cleaving enzyme (BACE1) in APP23 AD mouse model [109,110] (Fig. 2 (6)).…”

Section: Stress and Neuroinflammationmentioning

confidence: 98%

Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement

et al. 2022

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Retinoid X receptors (RXRs) present a subgroup of the nuclear receptor superfamily with particularly high evolutionary conservation of ligand binding domain. The receptor exists in α, β, and γ isotypes that form homo-/heterodimeric complexes with other permissive and non-permissive receptors. While research has identified the biochemical roles of several nuclear receptor family members, the roles of RXRs in various neurological disorders remain relatively under-investigated. RXR acts as ligand-regulated transcription factor, modulating the expression of genes that plays a critical role in mediating several developmental, metabolic, and biochemical processes. Cumulative evidence indicates that abnormal RXR signalling affects neuronal stress and neuroinflammatory networks in several neuropathological conditions. Protective effects of targeting RXRs through pharmacological ligands have been established in various cell and animal models of neuronal injury including Alzheimer disease, Parkinson disease, glaucoma, multiple sclerosis, and stroke. This review summarises the existing knowledge about the roles of RXR, its interacting partners, and ligands in CNS disorders. Future research will determine the importance of structural and functional heterogeneity amongst various RXR isotypes as well as elucidate functional links between RXR homo- or heterodimers and specific physiological conditions to increase drug targeting efficiency in pathological conditions.

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Rational Design, Synthesis, and In Vitro Neuroprotective Evaluation of Novel Glitazones for PGC-1α Activation via PPAR-γ: a New Therapeutic Strategy for Neurodegenerative Disorders

Cited by 24 publications

References 53 publications

Novel glitazone attenuates rotenone-induced toxicity in mouse model of Parkinson’s disease

Novel glitazone attenuates rotenone-induced toxicity in mouse model of Parkinson’s disease

Glitazones Activate PGC-1α Signaling via PPAR-γ: A Promising Strategy for Antiparkinsonism Therapeutics

Retinoid X Receptor: Cellular and Biochemical Roles of Nuclear Receptor with a Focus on Neuropathological Involvement

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