In vivo administration of urolithin A and B prevents the occurrence of cardiac dysfunction in streptozotocin-induced diabetic rats

Abstract

BackgroundEmerging evidence suggests that specific (poly)phenols may constitute new preventative strategies to counteract cell oxidative stress and myocardial tissue inflammation, which have a key role in the patho-physiology of diabetic cardiomyopathy. In a rat model of early diabetes, we evaluated whether in vivo administration of urolithin A (UA) or urolithin B (UB), the main gut microbiota phenolic metabolites of ellagitannin-rich foods, can reduce diabetes-induced microenvironmental changes in myocardial tissue, preventing cardiac functional impairment.MethodsAdult Wistar rats with streptozotocin-induced type-1 diabetes (n = 29) were studied in comparison with 10 control animals. Diabetic rats were either untreated (n = 9) or subjected to daily i.p. injection of UA (n = 10) or UB (n = 10). After 3 weeks of hyperglycaemia, hemodynamics, cardiomyocyte contractile properties and calcium transients were measured to assess cardiac performance. The myocardial expression of the pro-inflammatory cytokine fractalkine and proteins involved in calcium dynamics (sarcoplasmic reticulum calcium ATPase, phospholamban and phosphorylated phospholamban) were evaluated by immunoblotting. Plasma, urine and tissue distribution of UA, UB and their phase II metabolites were determined.ResultsIn vivo urolithin treatment reduced by approximately 30% the myocardial expression of the pro-inflammatory cytokine fractalkine, preventing the early inflammatory response of cardiac cells to hyperglycaemia. The improvement in myocardial microenvironment had a functional counterpart, as documented by the increase in the maximal rate of ventricular pressure rise compared to diabetic group (+18% and +31% in UA and UB treated rats, respectively), and the parallel reduction in the isovolumic contraction time (−12%). In line with hemodynamic data, both urolithins induced a recovery of cardiomyocyte contractility and calcium dynamics, leading to a higher re-lengthening rate (+21%, on average), lower re-lengthening times (−56%), and a more efficient cytosolic calcium clearing (−32% in tau values). UB treatment also increased the velocity of shortening (+27%). Urolithin metabolites accumulated in the myocardium, with a higher concentration of UB and UB-sulphate, potentially explaining the slightly higher efficacy of UB administration.ConclusionsIn vivo urolithin administration may be able to prevent the initial inflammatory response of myocardial tissue to hyperglycaemia and the negative impact of the altered diabetic milieu on cardiac performance.

The effect of folic acid administration on cardiac tissue matrix metalloproteinase activity and hepatorenal biomarkers in diabetic rats

“…Application of folic acid has positive effect on glucose level since it attenuates hyperglycaemia (however, glucose level values remained still higher than 11 mmol/l) in diabetic rats. DM type I is characterized by body mass loss (Gimenes et al 2015;Savi et al 2017). All our diabetic animals had decreased body mass, and the folic acid treatment did not have any influence on it.…”

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

“…This process leads to the production of urolithin A, urolithin B, urolithin C, and urolithin D. Urolithins have been shown to regulate cellular processes involved in normal and pathological conditions (Espín et al, ; Kang, Kim, Tomás‐Barberán, Espín, & Chung, ; Tang et al, ). A few recent studies have also reported that administration and consumption of these colonic metabolites, in particular urolithin A, promote positive health outcomes in animal models (Ryu et al, ; Savi et al, ; Tang et al, ). However and until now, the pharmacological effect of urolithins on endocrine pancreatic function has not been determined.…”

“…The multi‐target nature of urolithins as well as their effect on Ca 2+ signalling, at least for urolithin C, may possibly raise some concerns regarding their low selectivity and potential toxicity and thus constitute a drawback for their use in vivo. Nevertheless, until now, in vivo administration of urolithins failed to demonstrate any safety concerns (Heilman, Andreux, Tran, Rinsch, & Blanco‐Bose, ) but was rather found to exert a protective role and to ameliorate age‐related conditions (Ryu et al, ; Savi et al, ; Tang et al, ).…”

Urolithin A‐activated autophagy but not mitophagy protects against ischemic neuronal injury by inhibiting ER stress in vitro and in vivo

“…U847000) was dissolved in DMSO (50 mg/mL) and further diluted with saline immediately before intraperitoneal (ip) injections. Mice were given an intraperitoneal injection of 2.5 or 5.0 mg/kg of Uro‐A as previously described, for 24 hours and 1 hour before surgery. Mice were grouped into a sham, sham + Uro‐A, MCAO, and MCAO + Uro‐A groups.…”