Fluconazole Is Neuroprotective via Interactions with the IGF-1 Receptor
Valerie Toodle1, Myoung-Hwa Lee1, Muzna Bachani2
1Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 7C-103; Bldg. 10, 10 Center Drive, Bethesda, MD, 20892, USA.
Summary
The antifungal drug fluconazole shows neuroprotective effects against various toxins and promotes neural stem cell growth. This discovery offers a potential new therapeutic strategy for neurodegenerative disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- Neurodegenerative disorders present a significant unmet medical need.
- Developing effective neuroprotective strategies is crucial for treating these conditions.
Purpose of the Study:
- To identify novel compounds with neuroprotective properties.
- To investigate the potential of antifungal agents as treatments for neurodegenerative diseases.
Main Methods:
- Screened over 2000 compounds for neuroprotective activity in oxidative stress models.
- Characterized the efficacy of fluconazole in vitro and in vivo against various neurotoxins.
- Investigated the underlying molecular mechanisms involving insulin growth factor-1 receptor (IGF-1R) signaling.
Main Results:
- Identified numerous antifungal agents, including fluconazole, as neuroprotective.
- Fluconazole prevented cell death and neurite retraction induced by diverse toxins (e.g., 3-nitropropionic acid, N-methyl D-aspartate, 6-hydroxydopamine, HIV proteins Tat and gp120).
- Fluconazole promoted neural progenitor cell proliferation and mediated effects via IGF-1R signaling, decreasing cAMP and increasing Akt phosphorylation.
Conclusions:
- Fluconazole demonstrates significant neuroprotective potential against multiple insults.
- Fluconazole promotes neural progenitor cell proliferation, suggesting regenerative capabilities.
- Fluconazole's mechanism involves IGF-1R signaling, positioning it as a promising candidate for neurodegenerative disease treatment.
