Sepiapterin reverses the changes in gastric nNOS dimerization and function in diabetic gastroparesis

Background We have demonstrated previously that in vivo supplementation of tetrahydrobiopterin (BH4); a co-factor for neuronal nitric oxide synthase (nNOS) significantly restored delayed gastric emptying and attenuated nitrergic relaxation in diabetic rat. In this study, we have investigated whether supplementation of sepiapterin (SEP), a precursor for BH4 biosynthesis via salvage pathway restores gastric emptying and nitrergic system in female diabetic rats. Methods Diabetic rats (streptozotocin-induced) were supplemented with BH4 or SEP (20 mg kg(-1) body weight). Gastric nitrergic relaxation in the presence or absence of high glucose and SEP were measured by electric field stimulation. Gastric muscular strips from healthy or diabetic female rats were incubated in the presence or absence of high glucose, SEP and/or methotrexate (MTX). Nitric oxide release was measured colorimetrically by NO assay kit. The expression of nNOS alpha and dimerization was detected by Western blot. Key Results In vitro studies on gastric muscular tissues showed that MTX, an inhibitor of BH4 synthesis via salvage pathway, significantly decreased NO release. In vivo treatment with MTX reduced both gastric nitrergic relaxation and nNOS alpha dimerization. Supplementation of SEP significantly attenuated delayed gastric emptying in diabetic rats. In addition, SEP supplementation restored impaired nitrergic relaxation, gastric nNOS alpha protein expression, and dimerization in diabetic rats. Conclusions & Inferences The above data suggests that supplementation of SEP accelerated gastric emptying and attenuated reduced gastric nNOS alpha expression, and dimerization. Therefore, SEP supplementation is a potential therapeutic option for female patients of diabetic gastroparesis.