Abstract
BackgroundThe difficulty of finding new treatments for neurological diseases with great impact in our society like Alzheimer’s disease can be ascribed in part to the complexity of the nervous system and the lack of quick and cost-effective screening tools. Such tools could not only help to identify potential novel treatments, but could also be used to test environmental contaminants for their potential to cause neurotoxicity. It has been estimated that 5–10% of the anthropogenic chemicals are developmental neurotoxic (DNT) and exposure to DNT compounds has been linked to several neurological diseases. Within this study we were testing the applicability of a quick and cost-effective behavioural test using zebrafish embryos: the touch-evoked response assay, in this case, an assay evaluating the swimming response to a tap in the tail. Two acetylcholinesterase (AChE) inhibitors positive controls (paraoxon and huprine Y), as well as 10 huprine-derivative compounds were tested and the results were evaluated using 2 different methods, a quantitative and a qualitative one.ResultsWe could show that the methodology presented is able to detect behavioural effects of AChE inhibitors. A good correlation between the results obtained with the quantitative and the qualitative method was obtained (R2 = 0.84).ConclusionsOur proposed method enables combination of screening for new drugs with toxicity screening in a whole embryo model alternative to animal experimentation, thereby merging 2 drug development steps into one.
Highlights
The difficulty of finding new treatments for neurological diseases with great impact in our society like Alzheimer’s disease can be ascribed in part to the complexity of the nervous system and the lack of quick and costeffective screening tools
It has been proved that touch-evoked motility is severely impaired in acetylcholinesterase (AChE) mutant embryos whose AChE activity is completely abolished [13], as well as in embryos exposed to cholinergic blockers like α-bungarotoxin or d-tubocurarine, which suppress neuromuscular transmission in the zebrafish [14], but so far, it has not been used to evaluate the behavioural effects of new synthetic AChE inhibitors with potential pharmacological activity
We provide recommendations which will help to improve the use of this behavioural assay in zebrafish embryos for compounds with AChE inhibitory activity, and will facilitate future inter-laboratory comparison of results
Summary
The difficulty of finding new treatments for neurological diseases with great impact in our society like Alzheimer’s disease can be ascribed in part to the complexity of the nervous system and the lack of quick and costeffective screening tools. The zebrafish (Danio rerio) is a very promising model to study the effects of compounds at a neurological level, either in the neuropharmacological or in the neurotoxicological field This is because it allows the study of Guzman et al Environ Sci Eur (2020) 32:145 to animal experimentation up to 120 h post-fertilization (hpf ) [8, 9]. As AChE is the enzyme responsible for finalizing cholinergic activity in the synaptic cleft, AChE inhibition leads to a synaptic accumulation of the neurotransmitter acetylcholine (ACh) and results in an increased stimulation of cholinergic neurons This mechanism of action has been related to different pharmacological and toxicological effects: it is a desired effect in new potential treatments for Alzheimer’s disease because it is related with memory and learning processes or in new potential treatments for myasthenia gravis because of its functional effects at the neuromuscular junction. AChE inhibitors can be medical drugs or toxic compounds depending on their potency, their therapeutic index and the dose of exposure
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