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Suchismita Acharya, Courtney Weston, Dorette Z Ellis, Adnan Dibas; Novel small hybrid molecule with cytoprotective and IOP lowering activity. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2721.
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© ARVO (1962-2015); The Authors (2016-present)
Compromised trabecular meshwork (TM) health is one of the major reasons for inducing high intraocular pressure (IOP), oxidative stress and inflammation resulting in retinal ganglion cell (RGC) death in primary open angle glaucoma. The goal was to find an optimized novel small molecule with both antioxidant, and nitric oxide donating activity and test in vitro using TM cells for their cytoprotecting activity. The next goal was to test a slow release nanosuspension of the selected compound SA-9NP in an ocular hypertensive (OHT) mice model for IOP lowering activity.
In vitro activity: Human primary TM cells were treated with or without t-butyl hydrogen peroxide (TBHP, 300µM) for 30 minutes followed by treatment of compounds in either PBS solution (0.05µM-100µM), or nanosuspensions (0.01-1% w/v). MTT assay (Promega) was performed after 24 hours. Experiments were repeated thrice with 5-8 technical replicates. IOP lowering activity: C57BL/6J mice (9-10 months old) (n = 6 per group) were injected periocularly with Dexamethasone acetate (DEX, 20µL, 200µg/eye) in both eyes once a week for 4 weeks to elevate the IOP. Topical eye drops (6 µL) containing: A) Vehicle (PBS), B) SA-2NPs (2% w/v)-positive control or C) SA-9NPs (2% w/v) formulated in PBS were administered as a single eye drop. IOP was measured using the TonoLab rebound tonometer at 0, 3, 6, 24 and 72 h post-dosing.
TBHP induced ~50 % cell death in TM cells and compound SA-9 was potent (EC50 = 0.48 µM) in inhibiting the cell death and was superior than our previously reported compound SA-2 (EC50 = 20.3 µM). SA-9 demonstrated excellent safety profile in TM cells (200-fold over EC50). DEX injection elevated the IOP in both eyes (21.9 ± 5.92 mm/Hg) compared to baseline (11.85 ± 2.27 mm/Hg). A single topical eye drops of SA-9NPs significantly lowered IOP (13.33 ± 1.15 mm/Hg) and was superior than SA-2NPs (14.47 ± 3.06 mm/Hg) at 3h post-dose with the effect lasting >72 h (13.21 ± 1.68 mm/Hg for SA-2NPs and 12.22 ± 1.48 mm/Hg for SA-9NPs). *p<0.05, **p<0.005 respectively for 3 and 72 hrs vs OHT groups. N = 6-10 eyes.
Structure optimization resulted in more potent and efficacious compound SA-9 that was cytoprotective to damaged TM cells. SA-9 nanosuspension lowered IOP in DEX induced OHT mouse model with longer duration of action. This class of molecule has high potential to be useful for treatment of glaucoma.
This is a 2020 ARVO Annual Meeting abstract.
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