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Inhibitory effect of Nifedipine on aldose reductase delays cataract progression
Alaparthi Malini Devi1, Venu Sankeshi1, Arugonda Ravali1
1Drug Design & Molecular Medicine Laboratory, Department of Genetics & Biotechnology, Osmania University, Hyderabad, 500007, India.
Abstract:
Aldose reductase (ALR2) is a rate-limiting component of the polyol pathway, which is essential for the NADPH-mediated conversion from glucose to sorbitol. ALR2 dysregulation has been linked to α-crystallin aggregation, increased oxidative stress, and calcium inflow, all of which contribute to a diabetic cataract. Given its crucial role in occular pathologies, ALR2 has emerged as a promising target to treat oxidative stress and hyperglycaemic condition which form the underlying cause of diabetic cataracts. However, several of them had issues with sensitivity and specificity to ALR2, despite being screened as effective ALR2 inhibitors from a wide range of structurally varied molecules. The current study investigates the inhibitory potential of Nifedipine, an analog of the dihydro nicotinamide class of compounds against ALR2 activity. The enzyme inhibition studies were supported by in vitro biomolecular interactions, molecular modeling approaches, and in vivo validation in diabetic rat models. Nifedipine demonstrated appreciable inhibitory potential with the purified recombinant hAR (human aldose reductase; with an IC50 value of 2.5 µM), which was further supported by Nifedipine-hAR binding affinity (Kd = 2.91 ± 1.87 × 10-4 M) by ITC and fluorescence quenching assays. In the in vivo models of STZ-induced diabetic rats, Nifedipine delayed the onset progression of cataracts by preserving the antioxidant enzyme activity (SOD, CAT, and GPX GSH, TBARS, and protein carbonyls) and was shown to retain the α-crystallin chaperone activity by reducing the calcium levels in the diabetic rat lens. In conclusion, our results demonstrate effective inhibition of ALR2 by Nifedipine, resulting in amelioration of diabetic cataract conditions by lowering oxidative and osmotic stress while retaining the chaperone activity of α-crystallins. The present study could be envisaged to improve the eye condition in older adults upon Nifedipine treatment.
Insights
Nifedipine effectively inhibits aldose reductase (ALR2), a key enzyme in diabetic cataract formation. This compound reduces oxidative stress and preserves lens function, offering a potential treatment for diabetic eye disease.
Area of Science:
- Biochemistry
- Pharmacology
- Ophthalmology
Background:
- Aldose reductase (ALR2) is a critical enzyme in the polyol pathway, implicated in diabetic cataracts through oxidative stress and altered calcium homeostasis.
- Existing ALR2 inhibitors often lack sufficient sensitivity and specificity, highlighting the need for novel therapeutic agents.
- Diabetic cataracts are a significant cause of vision impairment in older adults, necessitating effective treatments targeting hyperglycaemic conditions.
Purpose of the Study:
- To investigate the inhibitory potential of Nifedipine, a dihydro nicotinamide analog, against aldose reductase (ALR2) activity.
- To evaluate the efficacy of Nifedipine in ameliorating diabetic cataract progression in vivo.
- To assess Nifedipine's impact on oxidative stress markers and lens protein function in a diabetic rat model.
Main Methods:
- Enzyme inhibition assays using purified recombinant human aldose reductase (hAR).
- In vitro biomolecular interaction studies, including isothermal titration calorimetry (ITC) and fluorescence quenching assays.
- In vivo validation in streptozotocin (STZ)-induced diabetic rat models to assess cataract progression and biochemical markers.
Main Results:
- Nifedipine demonstrated significant inhibitory potential against hAR with an IC50 of 2.5 µM and showed binding affinity (Kd = 2.91 × 10⁻⁴ M).
- In vivo studies showed Nifedipine delayed cataract onset and progression in diabetic rats.
- Nifedipine preserved antioxidant enzyme activity, reduced oxidative stress markers, and maintained α-crystallin chaperone activity by lowering intraocular calcium levels.
Conclusions:
- Nifedipine effectively inhibits aldose reductase (ALR2), mitigating key pathological features of diabetic cataracts.
- The compound reduces oxidative and osmotic stress while preserving the crucial chaperone function of α-crystallins in the lens.
- Nifedipine presents a promising therapeutic strategy for improving ocular health in individuals with diabetic complications.
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