Project Title:

Nuclear Receptor N R2 B1 Targeting In Glaucoma Via Nutritional Approach

Chief Investigator:

Dr Vivek Gupta

Co-Investigators:

Prof Stuart Graham, A/Prof MehdiMirzaei, Mr Viswanthram Palanivel

Aim

To investigate the therapeutic potential and molecular mechanisms of NR2B1 activation in the retina using its endogenous agonist and natural precursor for protection against retinal ganglion cell (RGC) degeneration in glaucoma.

Methods

We used in vivo mouse models of glaucoma which includes microbead-induced IOP elevation chronic model to test the effects of NR2B1 activation after administration of 9CDHROL. The downstream effects of the modulation of these proteins on the retinal biochemical networks in health and glaucoma conditions were examined. Retinal structure, function, and inflammation were assessed using pSTR/ERG recordings, OCT, histology, histone acetylation, immunofluorescence, and western blotting approaches.

Conclusion

Our results indicate that NR2B1 activation by its endogenous agonist and natural precursor confers robust neuroprotection in experimental glaucoma models. This identifies NR2B1 as a viable, translatable target for glaucoma therapy that needs further investigations.

 

Lay Summary of Outcomes

Glaucoma involves RGC degeneration along with optic nerve excavation. The mechanisms underlying this damage are not yet clear, however recent studies indicate that NR2B1 may play a role in the glaucoma pathogenesis and retinal ganglion cell degeneration in the disease. Our results indicate that modulating NR2B1 via its naturally occurring agonist may serve as a mechanism-based strategy in vision preservation and provide new avenues for glaucoma treatment. This opens new, safe, and nutrition-based ways to prevent vision loss in glaucoma.

 

Key results

Immunostaining of retinal sections and immunoblotting analysis revealed that NR2B1 receptor well expressed in the retina. It is well expressed in human postmortem tissues, and its expression is downregulated in glaucoma conditions. NR2B1 expression is

downregulated in glaucoma models. 9CDHROL administration improved positive scotopic threshold (pSTR) amplitudes, retinal ganglion cell (RGC) survival, and optic nerve integrity. Inflammatory changes examination revealed a significant suppression of microglial and astrocytic activation in glaucoma upon treatment with the NR2B1 agonist.

 

Implications for Clinical Practice/Science and Future Research

These findings open a novel therapeutic avenue by targeting NR2B1 via small molecule agonists. Future steps include validation in larger animal models, pharmacokinetic profiling, and preparation for clinical translation as a neuroprotective treatment adjunct in glaucoma. Studies will identify whether targeting of NR2B1 is protective only if the treatment is started before the injury or if it also protects the RGCs once the glaucoma injury has initiated.

 

This research project was funded by AVR in 2024