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Long-Term Functional Rescue of Trauma-Induced Vision Loss by a Novel, Small Molecule TrkB Activator
Shweta Modgil1, Christopher L Walker2, Micah A Chrenek1
1Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA 30322.
Biorxiv : the Preprint Server for Biology
|March 3, 2025
Summary
A new compound, HIFN, activates TrkB receptors to protect retinal neurons from injury. This novel TrkB activator offers a promising strategy for treating traumatic ocular injuries and preventing vision loss.
Area of Science:
- Neuroscience
- Ophthalmology
- Pharmacology
Background:
- Brain-derived neurotrophic factor (BDNF) signaling via TrkB receptors supports neuronal survival but has clinical limitations.
- Developing selective TrkB activators is crucial for treating neurodegenerative disorders and traumatic injuries.
- Previous work identified HIOC as a selective TrkB agonist for ocular trauma.
Purpose of the Study:
- To synthesize and evaluate a novel fluoropyridine analog of HIOC, named HIFN, as a TrkB activator.
- To assess the neuroprotective effects of HIFN in an animal model of ocular blast injury.
- To compare the efficacy of HIFN with its parent compound, HIOC.
Main Methods:
- Synthesis of 2-fluoro-N-(2-(5-hydroxy-1H-indol-3-yl) ethyl) nicotinamide (HIFN).
- In vivo testing in a mouse model of overpressure ocular blast injury.
- Assessment of visual function (visual acuity, contrast sensitivity), retinal function, and retinal ganglion cell survival.
- Pharmacological blockade of TrkB receptor using ANA-12.
Main Results:
- HIFN demonstrated potent TrkB activation, exceeding that of HIOC.
- HIFN treatment significantly ameliorated blast-induced visual functional decline.
- Mice treated with HIFN showed improved visual acuity, contrast sensitivity, and retinal function, with enhanced retinal ganglion cell survival.
- Neuroprotection by HIFN was dependent on TrkB activation, as confirmed by antagonist studies.
Conclusions:
- HIFN is a novel, potent TrkB receptor activator with significant neuroprotective effects against ocular blast injury.
- HIFN represents a promising therapeutic strategy for mitigating retinal degeneration and vision loss from traumatic eye injuries.
- The findings suggest potential broader applications for HIFN in conditions involving altered TrkB activity.
