Abstract
Acrylamide (ACR), a type-2 alkene, may lead to a synaptopathy characterized by ataxia, skeletal muscles weakness and numbness of the extremities in exposed human and laboratory animals. Currently, only the mildly affected patients undergo complete recovery, and identification of new molecules with therapeutic bioactivity against ACR acute neurotoxicity is urgently needed. Here, we have generated a zebrafish model for ACR neurotoxicity by exposing 5 days post-fertilization zebrafish larvae to 1 mM ACR for 3 days. Our results show that zebrafish mimics most of the pathophysiological processes described in humans and mammalian models. Motor function was altered, and specific effects were found on the presynaptic nerve terminals at the neuromuscular junction level, but not on the axonal tracts or myelin sheath integrity. Transcriptional markers of proteins involved in synaptic vesicle cycle were selectively altered, and the proteomic analysis showed that ACR-adducts were formed on cysteine residues of some synaptic proteins. Finally, analysis of neurotransmitters profile showed a significant effect on cholinergic and dopaminergic systems. These data support the suitability of the developed zebrafish model for screening of molecules with therapeutic value against this toxic neuropathy.
Highlights
Acrylamide (ACR) is a water-soluble alkene primarily used in the production of polyacrylamides
Studies by the LoPachin group demonstrated that the molecular initiating event of ACR neurotoxicity was the disruption of presynaptic vesicle cycling by selectively forming adducts with thiolate sites located on proteins involved in vesicle docking, vesicle priming, SNARE core dissolution (N-ethylmaleimide sensitive factor), endocytosis, neurotransmitter re-uptake and vesicular storage at the nerve terminals[4]
Any animal model suitable to be used in the identification of new drugs for treatment of ACR acute neurotoxicity should recapitulate the most relevant pathophysiological mechanisms in human[24], and currently no data are available about the sensitivity of zebrafish larvae to develop synaptotoxicity by acute exposure to ACR
Summary
Acrylamide (ACR) is a water-soluble alkene primarily used in the production of polyacrylamides. One key advantage of zebrafish embryos/larvae over other vertebrate models for drug discovery is their suitability for in vivo high-throughput screening of chemical libraries for pharmacological and/or toxicological effects. In this context, zebrafish has been proposed as an intermediate step between cell-based assays and mammalian (and human) testing. Any animal model suitable to be used in the identification of new drugs for treatment of ACR acute neurotoxicity should recapitulate the most relevant pathophysiological mechanisms in human[24], and currently no data are available about the sensitivity of zebrafish larvae to develop synaptotoxicity by acute exposure to ACR
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