Extensive depolarization and lack of recovery of leech Retzius neurons caused by 2,4 diaminobutyric acid

Spasić, Svetolik; Stanojević, Miroslav; Ostojic, Jelena Nesovic; Kovačević, Sanjin; Prostran, Milica; Lopičić, Srdjan

doi:10.1016/j.aquatox.2018.03.036

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…Although 2,4-DAB can also agonize NMDA receptors and depolarize neurons (Spasic et al 2018), we did not observe the same hypersensitive startle phenotype in 2,4-DABexposed zebrafish larvae. Rather, we observed that 2,4-DAB modulates startle kinematics, suggesting that 2,4-DAB acts through distinct mechanisms to cause neurotoxicity.…”

Section: Discussioncontrasting

confidence: 83%

“…Another in vitro study found that 2,4-DAB and BMAA exerted similar levels of toxicity in decreasing the viability of human neuroblastoma cells ( Main et al 2018 ). Like BMAA, 2,4-DAB also activates N-methyl-D-aspartate (NMDA) receptors ( Spasic et al 2018 ), a mode of action that is also a primary mechanism of BMAA-induced neurotoxicity ( Lobner 2009 ). These in vitro studies recognize the neurotoxic potential of 2,4-DAB and AEG and highlight the importance of examining their individual and potential combined effects with BMAA in vivo.…”

Section: Introductionmentioning

confidence: 99%

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The Cyanotoxin 2,4-DAB Reduces Viability and Causes Behavioral and Molecular Dysfunctions Associated with Neurodegeneration in Larval Zebrafish

2022

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Exposure to cyanotoxins has been linked to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s disease. While the cyanotoxin β-methylamino-L-alanine (BMAA) has received much attention, cyanobacteria produce many cyanotoxic compounds, several of which have been detected in nature alongside BMAA, including 2,4-diaminobutyric acid (2,4-DAB) and N-(2-aminoethyl)glycine (AEG). Thus, the question of whether 2,4-DAB and AEG also cause neurotoxic effects in vivo is of great interest, as is the question of whether they interact to enhance toxicity. Here, we evaluate the toxic and neurotoxic effects of these cyanotoxins alone or in combination by measuring zebrafish larval viability and behavior after exposure. 2,4-DAB was the most potent cyanotoxin as it decreased larval viability by approximately 50% at 6 days post fertilization, while BMAA and AEG decreased viability by just 16% and 8%, respectively. Although we only observed minor neurotoxic effects on spontaneous locomotion, BMAA and AEG enhanced acoustic startle sensitivity, and they interacted in an additive manner to exert their effects. 2,4-DAB; however, only modulated startle kinematics, an indication of motor dysfunction. To investigate the mechanisms of 2,4-DAB’s effects, we analyzed the protein profile of larval zebrafish exposed to 500 µM 2,4-DAB at two time points and identified molecular signatures consistent with neurodegeneration, including disruption of metabolic pathways and downregulation of the ALS-associated genes SOD1 and UBQLN4. Together, our data demonstrate that BMAA and its isomers AEG and 2,4-DAB cause neurotoxic effects in vivo, with 2,4-DAB as the most potent of the three in the zebrafish model.

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Section: Discussioncontrasting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

The Cyanotoxin 2,4-DAB Reduces Viability and Causes Behavioral and Molecular Dysfunctions Associated with Neurodegeneration in Larval Zebrafish

2022

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“…Although 2,4-DAB can also agonize NMDA receptors and depolarize neurons (Spasic et al 2018), we did not observe the same hypersensitive startle phenotype in 2,4-DAB-exposed zebrafish larvae. Rather, we observed that 2,4-DAB modulates startle kinematics, suggesting that 2,4-DAB acts through distinct mechanisms to cause neurotoxicity.…”

Section: Discussioncontrasting

confidence: 83%

“…The performance of SLC responses, defined through kinematic parameters such as curvature, angular velocity, and duration, depends on the proper function of the underlying motor circuits in the hindbrain and spinal cord, along with that of axial muscles. If startle kinematic defects are observed, this is an indication of motor dysfunction (Spasic et al 2018). As 2,4-DAB did not alter the frequency or latency of SLCs, in contrast to BMAA and AEG, but instead impacted curvature, angular velocity, and duration (Figure 5), 2,4-DAB likely acts downstream of the command-like Mauthner neurons.…”

Section: Discussionmentioning

confidence: 95%

“…A recent in vitro study revealed that the isomer AEG is a more potent neurotoxin than BMAA and that the toxicity of AEG is mediated by the induction of free radicals as well as the activation of metabotropic glutamate receptors (i.e., mGluR5) (Schneider et al 2020). Like BMAA, 2,4-DAB activates N-methyl-D-aspartate (NMDA) receptors (Spasic et al 2018), a mode of action this is also a primary mechanism of BMAA-induced neurotoxicity (Lobner 2009).…”

Section: Introductionmentioning

confidence: 99%

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The cyanotoxin 2,4-DAB enhances mortality and causes behavioral and molecular dysfunctions associated with neurodegeneration in larval zebrafish

Martin

Bereman

Marsden

2021

Preprint

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Exposure to cyanotoxins has been linked to neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. While the cyanotoxin beta-methylamino-L-alanine (BMAA) has received much attention, cyanobacteria produce many cyanotoxic compounds, several of which have been detected in nature alongside BMAA including 2,4-diaminobutyric acid (2,4-DAB), and N-(2-aminoethyl)glycine (AEG). Thus, the question of whether DAB and AEG also cause neurotoxic effects in vivo is of great interest, as is the question of whether they interact to enhance toxicity. Here, we evaluate the toxic and neurotoxic effects of these cyanotoxins alone or in combination by measuring zebrafish larval viability and behavior after exposure. 2,4-DAB was the most potent cyanotoxin as it decreased larval viability by approximately 50% at 6 days post fertilization, while BMAA and AEG decreased viability by just 16% and 8%, respectively. Although we only observed minor neurotoxic effects on spontaneous locomotion, BMAA and AEG enhanced acoustic startle sensitivity, and they interacted in an additive manner to exert their effects. 2,4-DAB, however, only modulated the startle kinematics, an indication of motor dysfunction. To investigate the mechanisms of 2,4-DAB's effects, we analyzed the protein profile of larval zebrafish exposed to 500 uM 2,4-DAB at two time points and identified molecular signatures consistent with neurodegeneration, including disruption of metabolic pathways and downregulation of the ALS-associated genes SOD1 and UBQLN4. Together, our data demonstrate that BMAA and its isomers AEG and 2,4-DAB cause neurotoxic effects in vivo, with 2,4-DAB as the most potent of the three in the zebrafish model.

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Two distinct electrophysiological mechanisms underlie extensive depolarization elicited by 2,4 diaminobutyric acid in leech Retzius neurons

et al. 2020

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Extensive depolarization and lack of recovery of leech Retzius neurons caused by 2,4 diaminobutyric acid

Cited by 7 publications

References 35 publications

The Cyanotoxin 2,4-DAB Reduces Viability and Causes Behavioral and Molecular Dysfunctions Associated with Neurodegeneration in Larval Zebrafish

The Cyanotoxin 2,4-DAB Reduces Viability and Causes Behavioral and Molecular Dysfunctions Associated with Neurodegeneration in Larval Zebrafish

The cyanotoxin 2,4-DAB enhances mortality and causes behavioral and molecular dysfunctions associated with neurodegeneration in larval zebrafish

Two distinct electrophysiological mechanisms underlie extensive depolarization elicited by 2,4 diaminobutyric acid in leech Retzius neurons

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