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Published on: March 20, 2012
Embryonic exposure to acetyl-L-carnitine protects against valproic acid-induced cardiac malformation in zebrafish
Venugopalan Rajesh1, Annadurai Kokilavani2, Subramanian Jayaseelan3
1Department of Pharmacology, The Erode College of Pharmacy and Research Institute, Veppampalayam, Vallipurathampalayam (Po), Erode, Tamil Nadu, 638112, India. rajeshcology@rediffmail.com.
Insights
Prenatal exposure to valproic acid (VPA) causes birth defects, including heart malformations in zebrafish. Acetyl-L-carnitine (AC) treatment significantly improved cardiac development and function, suggesting it can counteract VPA-induced damage.
Area of Science:
- Developmental Biology
- Toxicology
- Cardiovascular Research
Background:
- Congenital malformations affect millions of children globally, with prenatal drug exposure being a significant cause.
- Valproic acid (VPA) is a known teratogen that can induce cardiac malformations.
- The carnitine shuttle is crucial for cardiac energy metabolism, relying on fatty acid oxidation.
Purpose of the Study:
- To investigate the protective effects of acetyl-L-carnitine (AC) against valproic acid (VPA)-induced cardiac malformations in developing zebrafish.
- To evaluate the impact of AC on cardiac morphology, function, and apoptosis following VPA exposure.
Main Methods:
- Zebrafish embryos were exposed to a sub-lethal concentration of VPA (50 µM) to induce cardiac malformations.
- Acetyl-L-carnitine (AC) at 25 µM and 50 µM concentrations was administered to assess its protective effects.
- Cardiac development, function, morphology, histology, and apoptosis were monitored at various time points post-fertilization (hpf).
Main Results:
- VPA exposure led to progressive cardiac dysfunction, abnormal heart morphology (elongated chambers), and increased apoptosis.
- Co-administration of VPA with 50 µM AC significantly reduced pericardial edema and improved cardiac morphology and function.
- AC treatment also decreased the number of apoptotic cells, indicating a protective effect against VPA-induced cell death.
Conclusions:
- Acetyl-L-carnitine (AC) demonstrates significant protective effects against valproic acid (VPA)-induced cardiac malformations in zebrafish.
- AC may restore carnitine homeostasis, supporting cardiac energy metabolism and mitigating VPA's teratogenic effects.
- This study highlights AC as a potential therapeutic agent for preventing or treating drug-induced congenital heart defects.
Abstract:
Worldwide, estimated counts of about 7.9 million children are born with serious birth defects. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants represents a major contributing factor to congenital malformations. In earlier investigation, we explored cardiac malformation caused by valproic acid (VPA) during early developing stages of zebrafish. Since heart depends on mitochondrial fatty acid oxidative metabolism for energy demands in which carnitine shuttle has a major role, the present study aimed to investigate the effect of acetyl-L-carnitine (AC) against VPA-induced cardiac malformation in developing zebrafish. Initially, AC was subjected to toxicological evaluation, and two micromolar concentrations (25 µM and 50 µM) were selected for evaluation. A sub-lethal concentration of VPA (50 µM) was selected to induce cardiac malformation. The embryos were grouped and the drug exposures were made at 2.5 h post-fertilization (hpf). The cardiac development and functioning was monitored. A progressive decline in cardiac functioning was noted in group exposed to VPA 50 µM. At 96 hpf and 120 hpf, the morphology of heart was severely affected with the chambers which became elongated and string-like accompanied by histological changes. Acridine orange staining showed accumulation of apoptotic cells. Group exposed to VPA 50 µM with AC 50 µM showed a significant reduction in pericardial sac edema with morphological, functional and histological recovery in developing heart. Moreover, reduced number of apoptotic cells was noted. The improvement with AC might be due to restoration of carnitine homeostasis for cardiac energy metabolism in developing heart.
