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Experimental Models to Study the Neuroprotection of Acidic Postconditioning Against Cerebral Ischemia
Published on: July 31, 2017
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Thioflavones as novel neuroprotective agents.
Divyashree Ravishankar1, Giulia Corona2, Stephanie M Hogan1
1School of Pharmacy, University of Reading, Whiteknights, RG6 6AD Berkshire, UK.
Bioorganic & Medicinal Chemistry
|September 25, 2016
Summary
New synthetic 7,8-dihydroxy 4-thioflavones show significant neuroprotection against oxidative stress by activating cell survival pathways. Specific compounds 14d and 18d were most effective, highlighting potential therapeutic agents for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Medicinal Chemistry
Background:
- Oxidative stress is a key factor in neurodegenerative disease pathology.
- Developing small molecules for neuroprotection is crucial for therapeutic interventions.
Purpose of the Study:
- To evaluate a library of flavone derivatives for neuroprotective properties against hydrogen peroxide-induced oxidative stress.
- To identify specific compounds and elucidate their mechanism of action and structure-activity relationships.
Main Methods:
- Screening of 76 hydroxy flavones, methoxy flavones, and their 4-thio analogues for neuroprotection.
- Assessing neuroprotection against H2O2-induced oxidative stress in relevant cellular models.
- Investigating the involvement of ERK1/2 and PI3K/Akt signaling pathways.
- Conducting structure-activity relationship (SAR) analysis.
Main Results:
- Synthetic 7,8-dihydroxy 4-thioflavones demonstrated significant neuroprotective effects.
- Compounds 14d and 18d exhibited the highest potency at low concentrations (0.3μM).
- Neuroprotection was mediated by activating the anti-apoptotic ERK1/2 and PI3K/Akt cell survival pathways.
- The B-ring phenyl group was essential for enhanced neuroprotection, and replacing the 4-CO with a 4-CS moiety generally improved efficacy.
Conclusions:
- 7,8-dihydroxy 4-thioflavones represent a promising class of neuroprotective agents.
- The identified compounds exert their effects through modulation of key cell survival signaling pathways.
- SAR analysis provides valuable insights for the design of novel neuroprotective flavone derivatives.
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