Vitamin A ameliorates valproic acid-induced autism-like symptoms in developing zebrafish larvae by attenuating oxidative stress and apoptosis

Introduction

The causes of ASD are not fully understood, but genetic and environmental factors are believed to play a role. One of the environmental factors that has been linked to ASD is prenatal exposure to valproic acid (VPA), a drug used to treat epilepsy and bipolar disorder. VPA can induce autism-like symptoms in animal models, such as mice and rats. However, these models have limitations, such as high cost, ethical issues, and low throughput.

 

Zebrafish (Danio rerio) is an emerging model organism for studying neurodevelopmental disorders, such as ASD. Zebrafish have many advantages, such as high fecundity, transparency, genetic manipulability, and behavioral similarity to humans. Previous studies have shown that VPA can induce autism-like symptoms in zebrafish larvae, such as reduced social interaction, increased anxiety, and impaired learning and memory. However, the molecular mechanisms underlying VPA-induced ASD are still unclear.

 

Vitamin A (VA) is an essential micronutrient that plays a crucial role in neurodevelopment and neuroprotection. VA deficiency can cause various neurological disorders, such as cognitive impairment, schizophrenia, and depression. VA can also modulate oxidative stress and apoptosis, which are implicated in the pathogenesis of ASD. However, the effects of VA on VPA-induced ASD have not been explored.

 

The aim of this study was to investigate whether VA can ameliorate VPA-induced autism-like symptoms in developing zebrafish larvae by attenuating oxidative stress and apoptosis.

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Methods

The authors used zebrafish embryos obtained from wild-type AB strain adults. The embryos were exposed to VPA (0.5 mM) or VA (0.1 mM) or both from 2 hours post-fertilization (hpf) to 6 days post-fertilization (dpf). The control group was exposed to vehicle (0.1% DMSO). The authors performed various behavioral, biochemical, and molecular assays to evaluate the effects of VPA and VA on zebrafish larvae.

 

Results

The authors found that VPA exposure reduced the survival rate, body length, and body weight of zebrafish larvae, while VA exposure had no significant effect. However, VA co-treatment significantly improved the survival rate, body length, and body weight of VPA-exposed larvae.

 

The authors also found that VPA exposure impaired the social interaction of zebrafish larvae, as measured by the shoaling test. VPA-exposed larvae spent less time and distance near their conspecifics than the control group. VA co-treatment significantly increased the time and distance spent near conspecifics by VPA-exposed larvae, indicating improved social interaction.

 

Furthermore, the authors found that VPA exposure increased the anxiety-like behavior of zebrafish larvae, as measured by the novel tank test. VPA-exposed larvae spent more time and distance in the bottom half of the tank than the control group, indicating increased fear and avoidance. VA co-treatment significantly reduced the time and distance spent in the bottom half of the tank by VPA-exposed larvae, indicating reduced anxiety-like behavior.

 

Additionally, the authors found that VPA exposure impaired the learning and memory of zebrafish larvae, as measured by the T-maze test. VPA-exposed larvae showed lower preference for the previously rewarded arm than the control group, indicating impaired spatial memory. VA co-treatment significantly increased the preference for the previously rewarded arm by VPA-exposed larvae, indicating improved learning and memory.

 

Moreover, the authors found that VPA exposure induced oxidative stress and apoptosis in the brain of zebrafish larvae, as evidenced by increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), and caspase-3 activity, and decreased levels of glutathione (GSH) and superoxide dismutase (SOD) activity. VA co-treatment significantly reduced the levels of ROS, MDA, and caspase-3 activity, and increased the levels of GSH and SOD activity in the brain of VPA-exposed larvae, indicating attenuated oxidative stress and apoptosis.

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Finally, the authors found that VPA exposure altered the expression of several genes related to ASD, such as BDNF, SHANK3, MECP2, and RELN, in the brain of zebrafish larvae. VA co-treatment significantly normalized the expression of these genes in the brain of VPA-exposed larvae, indicating restored gene expression.

 

Conclusion

The authors concluded that VA can ameliorate VPA-induced autism-like symptoms in developing zebrafish larvae by attenuating oxidative stress and apoptosis. They suggested that VA may be a potential therapeutic agent for ASD. They also highlighted the advantages of using zebrafish as a model for studying ASD.

 

Additional Notes

  • The study was conducted using zebrafish larvae, which are a common model organism for studying developmental disorders.
  • The authors used a relatively high dose of vitamin A in their study. It is not clear whether lower doses would be effective.
  • More research is needed to determine the safety and efficacy of vitamin A treatment for autism in humans.

 

FAQ

What is the zebrafish model?

 

The zebrafish model is a widely used animal model for studying human diseases and disorders. Zebrafish share many genetic and physiological similarities with humans, making them an ideal model for studying neurodevelopmental disorders such as autism spectrum disorder (ASD).

 

What are the symptoms of ASD in zebrafish?

 

The symptoms of ASD in zebrafish include reduced locomotion, decreased distance near conspecifics, impaired social interaction, and repetitive swimming behaviors.

 

What is valproic acid (VPA)?

 

Valproic acid (VPA) is a medication that is commonly used to treat epilepsy, bipolar disorder, and migraine headaches. However, prenatal exposure to VPA has been reported to induce ASD-like symptoms in humans and rodents.

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What is the mechanism of action of valproic acid (VPA)?

 

Valproic acid (VPA) is an antiepileptic drug that works by increasing the levels of gamma-aminobutyric acid (GABA) in the brain. GABA is a neurotransmitter that helps to regulate brain activity.

 

What is oxidative stress?

 

Oxidative stress is a condition that occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify them. ROS are highly reactive molecules that can damage cells and tissues, leading to a variety of health problems.

 

What is apoptosis?

 

Apoptosis is a process of programmed cell death that occurs naturally in the body. It is a tightly regulated process that helps to remove damaged or unwanted cells from the body.

 

What is the mechanism of action of vitamin A?

 

Vitamin A is a potent antioxidant that can neutralize reactive oxygen species (ROS) and prevent oxidative damage to cells and tissues. It also regulates gene expression and plays a critical role in the development and function of the nervous system.

 

How does vitamin A help to prevent ASD-like symptoms?

 

Vitamin A helps to prevent ASD-like symptoms by reducing oxidative stress and apoptosis. Oxidative stress is a type of cell damage that can lead to cell death, and apoptosis is a programmed cell death process. Vitamin A helps to protect cells from oxidative stress and apoptosis, which can help to prevent the development of ASD-like symptoms.

 

What are the potential side effects of vitamin A supplementation?

 

High doses of vitamin A can be toxic and cause a range of adverse effects, including nausea, vomiting, headache, dizziness, blurred vision, and liver damage. Therefore, it is important to follow the recommended daily intake of vitamin A and avoid excessive supplementation.

 

What are the limitations of this study?

 

This study was conducted on zebrafish, and it is not clear whether the results would be the same in humans. Additionally, the study only looked at the effects of vitamin A on VPA-induced ASD-like symptoms, and it is not clear whether vitamin A would be effective in treating other forms of ASD.

 

Source:

https://www.sciencedirect.com/science/article/abs/pii/S0161813X23001869

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