Abstract
The plant-derived natural alkaloid berberine displays therapeutic potential to treat several pathological conditions, including dyslipidemias, diabetes and cardiovascular disorders. However, data on berberine effects during embryonic development are scarce and in part controversial. In this study, using zebrafish embryos as vertebrate experimental model, we address the effects of berberine treatment on cardiovascular system development and functionality. Starting from the observation that berberine induces developmental toxicity and pericardial edema in a time- and concentration-dependent manner, we found that treated embryos display cardiac looping defects and, at later stages, present an abnormal heart characterized by a stretched morphology and atrial endocardial/myocardial detachment. Furthermore, berberine affected cardiac functionality of the embryos, promoting bradycardia and reducing the cardiac output, the atrial shortening fraction percentage and the atrial stroke volume. We also found that, during development, berberine interferes with the angiogenic process, without altering vascular permeability. These alterations are associated with increased levels of vascular endothelial growth factor aa (vegfaa) mRNA, suggesting an important role for Vegfaa as mediator of berberine-induced cardiovascular defects. Altogether, these data indicate that berberine treatment during vertebrate development leads to an impairment of cardiovascular system morphogenesis and functionality, suggesting a note of caution in its use during pregnancy and lactation.
Highlights
Plant-derived natural compounds are important sources of medicinal agents to design new therapeutic strategies and are commonly considered effective and s afe[1]
BRB is considered a compound with a good safety profile and a high therapeutic potential, a certain degree of toxicity, genotoxicity, mutagenicity, carcinogenicity and cardiotoxicity of BRB have been reported in several experimental models in vitro and in vivo, indicating that the safety of this nutraceutical is strictly dependent on the experimental model, the route and duration of administration, as well as the concentration/dose used[6]
We initially evaluated the effects of increasing concentrations of BRB (50, 100, 200 and 400 mg/L) on survival rate (Fig. 1a, Supplementary Table S1) and induction of pericardial edema (Fig. 1b,c, Supplementary Table S2) in zebrafish embryos at different developmental stages (48, 72, 96, and 120 hpf), starting the treatment at 24 hpf
Summary
Plant-derived natural compounds are important sources of medicinal agents to design new therapeutic strategies and are commonly considered effective and s afe[1]. Other works indicated that BRB did not induce developmental toxicity, as previously shown in vitro in m ouse[25] and porcine early e mbryos[26] In this line, BRB increased clinical pregnancy rate and promoted the survival away from the nest following the transplantation of in vitro developed early mouse embryos[25] and continuous intragastric administration of Chinese Goldthread rhizome decoction, which contains BRB, or pure BRB to pregnant rats and mice did not cause abortion and developmental toxicity[27]. Previous results suggested that BRB may modulate the angiogenic process during development, as reported, for instance, in murine embryonic stem cell-derived embryoid bodies[35,36] and developing zebrafish e mbryos[14]. Zebrafish is a well-known and widely accepted experimental model to study the cardiovascular system development and functionality in vertebrates, both in physiological and pathological conditions[28,29,38]
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