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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

  • Antony Justin
  • Subhankar Mandal
  • P. Prabitha
  • S. Dhivya
  • S. Yuvaraj
  • Pradeep Kabadi
  • Satheesh John Sekhar
  • C. H. Sandhya
  • Ashish D. Wadhwani
  • Selvaraj Divakar
  • Jeyabalan Jeyaram Bharathi
  • Priya Durai
  • B. R. Prashantha KumarEmail author
Original Article

Abstract

In the present study, two structurally diverse novel glitazones were designed and synthesized for activation of central PGC-1α signaling through stimulation of PPAR-γ receptor. The functional interaction between PGC-1α and PPAR-γ is a key interaction in the normal physiology of neuroprotective mechanism. Therefore, activation of PPAR-γ–dependent PGC-1α co-activator signaling could be an effective strategy to exhibit neuroprotection in several neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and cerebral ischemia. As part of rational design, analogs were designed manually based on principles of bioisosterism, followed by virtually screened using docking to predict the mode of interaction of compound towards the binding site and molecular dynamic simulation to observe the structural changes that occur during compound interaction with active site. The designed two glitazones (G1, G2) were synthesized and structurally analyzed. As part of evaluation, synthesized glitazones were subjected for preliminary neuroprotective evaluation in Lipopolysaccharide (LPS) intoxicated SH-SY5Y neuroblastoma cells. The results indicate that pre-treatment with synthesized glitazones have increased the percentage cell viability, protected the cell morphology, and decreased the release of pro-inflammatory cytokines (IL-1β, TNF-α), lipid peroxide (LPO), and nitric oxide (NO) level in LPS intoxicated SH-SY5Y cells. Interestingly, among the two glitazones, G2 has shown significant neuroprotection in comparison to G1 and neuroprotective effect exerted by G2 was similar and comparable with the standard pioglitazone. Altogether, neuroprotection exhibited by this non-thiazolidione–based glitazones during neuroinflammatory conditions may be attributed to the activation of central PGC-1α signaling via PPAR-γ receptor.

Keywords

PGC-1α PPAR-γ Glitazones Docking Molecular dynamic simulation Cytokines Free radicals 

Notes

Funding Information

The authors sincerely thank the Department of Science and Technology—Science and Engineering Research Board (DST-SERB), New Delhi for extended financial support to carry out this project (Grant Sanction order No. CRG/2018/002084).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interest.

Supplementary material

12640_2019_132_MOESM1_ESM.doc (492 kb)
ESM 1 (DOC 492 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Antony Justin
    • 1
  • Subhankar Mandal
    • 2
  • P. Prabitha
    • 2
  • S. Dhivya
    • 2
  • S. Yuvaraj
    • 2
  • Pradeep Kabadi
    • 3
  • Satheesh John Sekhar
    • 1
  • C. H. Sandhya
    • 1
  • Ashish D. Wadhwani
    • 1
  • Selvaraj Divakar
    • 1
  • Jeyabalan Jeyaram Bharathi
    • 1
  • Priya Durai
    • 2
  • B. R. Prashantha Kumar
    • 2
    Email author
  1. 1.Department of PharmacologyJSS College of PharmacyOotyIndia
  2. 2.Department of Pharmaceutical ChemistryJSS College of PharmacyMysuruIndia
  3. 3.Bioanalytical DivisionBiocon Pvt. LtdBengaluruIndia

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