sepiapterin and Body-Weight

In the current study, we have investigated whether low density lipoprotein receptor knockout mice (LDLR-KO), moderate oxidative stress model and cholesteremia burden display gastroparesis and if so whether nitrergic system is involved in this setting. In addition, we have investigated if sepiapterin (SEP) supplementation attenuated impaired nitrergic system and delayed gastric emptying.. Gastric emptying and nitrergic relaxation were measured in overnight fasting mice. nNOSα dimerization, anti-oxidant markers such as Nrf2, GCLM, GCLC, HO-1, catalase (CAT), and superoxide dismutase (SOD1) were measured using standard methods. Biopterin levels and intestinal transit time were measured using HPLC and dye migration assay, respectively. Wild type (WT) and LDLR-KO were supplemented with SEP.. In LDLR null stomachs: (i) significant reduction in rate of gastric emptying, gastric pyloric and fundus nitrergic relaxation and nNOSα dimerization, (ii) elevated oxidized biopterins and reduced ratio of BH(4) /BH(2)  + B, (iii) reduced Nrf2 and GCLC protein expression and no change in GCLM, HO-1, CAT, SOD1, and (iv) accelerated small intestinal motility were noticed. Supplementation of SEP restored delayed gastric emptying, impaired pyloric and fundus nitrergic relaxation with restoration of nNOS dimerization and nNOS expression.. This novel data suggests that hyperlipidemia and/or suppression of selective antioxidants may be a potential cause of developing gastroparesis in diabetic patients.

Topics: Animals; Antioxidants; Biopterins; Blood Glucose; Body Weight; Female; Gastric Emptying; Gastrointestinal Motility; Gastroparesis; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Nitric Oxide; Nitric Oxide Synthase Type I; Oxidative Stress; Pterins; Receptors, LDL

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.. 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 nNOSα and dimerization was detected by Western blot.. 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 nNOSα dimerization. Supplementation of SEP significantly attenuated delayed gastric emptying in diabetic rats. In addition, SEP supplementation restored impaired nitrergic relaxation, gastric nNOSα protein expression, and dimerization in diabetic rats.. The above data suggests that supplementation of SEP accelerated gastric emptying and attenuated reduced gastric nNOSα expression, and dimerization. Therefore, SEP supplementation is a potential therapeutic option for female patients of diabetic gastroparesis.

Topics: Animals; Blood Glucose; Body Weight; Diabetic Neuropathies; Dietary Supplements; Dimerization; Female; Gastric Emptying; Gastroparesis; Immunosuppressive Agents; Male; Methotrexate; Nitric Oxide Synthase Type I; Protein Structure, Quaternary; Pterins; Rats; Rats, Sprague-Dawley; Stomach