Sulpiride increases intraocular vasoinhibin and protects against diabetic retinopathy in rats

Abstract

Purpose : Diabetic retinopathy (DR) an ocular complication of diabetes, is the leading cause of irreversible blindness and visual impairment among the working-age population. In DR, damage to the retinal microvasculature results in excessive vasopermeability and vascular proliferation (angiogenesis) that compromise vision. Vasoinhibin belongs to a family of proteins generated by the proteolytic cleavage of the hormone prolactin (PRL) that inhibit ischemia-induced retinal angiogenesis and diabetes-induced retinal vasopermeability. We used sulpiride, a dopamine type 2 receptor antagonist to induce hyperprolactinemia and tested the hypothesis that high levels of systemic PRL result in the increase of ocular vasoinhibin capable of counteract the progression of DR.

Methods : Experimental diabetes was induced in Wistar rats by an intraperitoneal (i.p.) injection of streptozotocin (STZ; 60 mg/kg) and four weeks after STZ, sulpiride was administered daily (20 mg/kg; i.p.) for two weeks. At the sixth week of diabetes, serum and retinas were collected, PRL or vasoinhibin were quantified by ELISA and Western-blot respectively, and retinal vasopermeability was assessed by the retinal leakage of Evans blue-stained albumin. To validate whether the effect of sulpiride was due to PRL, osmotic minipumps delivering PRL were implanted in four-weeks diabetic rats and after two weeks, the retinal vasopermeability was measured by the Evans blue assay.

Results : Sulpiride increased serum PRL in both diabetic (3.70±1.2 vs. 50.05±5.9 ng/ml) and non-diabetic rats (9.43±2.26 vs. 205.84±19.20 ng/ml), increased retinal vasoinhibin and reduced diabetes-induced retinal vasopermeability. PRL treatment also inhibited the increase of diabetes-induced retinal vasopermeability. Neither sulpiride nor PRL treatment modified blood glucose levels and body weight in rats.

Conclusions : Sulpiride is a prokinetic drug currently used in diabetic patients that may represent a promising therapy for DR due to its hyperprolactinemic effect leading to the increase of intraocular vasoinhibin. Supported by UNAM grant UR405PC.

This is a 2020 ARVO Annual Meeting abstract.