Augmentation and ionic mechanism of effect of β-N-methylamino-l-alanine in presence of bicarbonate on membrane potential of Retzius nerve cells of the leech Haemopis sanguisuga

Lopičić, Srdjan; Nedeljkov, Vladimir; Cemerikic, Dusan

doi:10.1016/j.cbpa.2009.02.038

Cited by 19 publications

(10 citation statements)

References 40 publications

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“…Consequently, an increase in intracellular Na + concentration and a decrease in intracellular K + concentration occur. These data suggest that BMAA could initiate excitotoxic mechanisms by activation of other non-NMDA ionotropic receptors [ 28 ]. All these data point out that the toxin acts in vitro on neurons by mechanisms involving overactivation of glu receptors ( Figure 2 ).…”

Section: Bmaa-induced Excitotoxicity Through Glutamate Receptorsmentioning

confidence: 99%

Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy

Delcourt

Claudepierre

Maignien

et al. 2017

Toxins

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The implication of the cyanotoxin β-N-methylamino-l-alanine (BMAA) in long-lasting neurodegenerative disorders is still a matter of controversy. It has been alleged that chronic ingestion of BMAA through the food chain could be a causative agent of amyotrophic lateral sclerosis (ALS) and several related pathologies including Parkinson syndrome. Both in vitro and in vivo studies of the BMAA mode of action have focused on different molecular targets, demonstrating its toxicity to neuronal cells, especially motoneurons, and linking it to human neurodegenerative diseases. Historically, the hypothesis of BMAA-induced excitotoxicity following the stimulation of glutamate receptors has been established. However, in this paradigm, most studies have shown acute, rather than chronic effects of BMAA. More recently, the interaction of this toxin with neuromelanin, a pigment present in the nervous system, has opened a new research perspective. The issues raised by this toxin are related to its kinetics of action, and its possible incorporation into cellular proteins. It appears that BMAA neurotoxic activity involves different targets through several mechanisms known to favour the development of neurodegenerative processes.

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Section: Bmaa-induced Excitotoxicity Through Glutamate Receptorsmentioning

confidence: 99%

Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy

Delcourt

Claudepierre

Maignien

et al. 2017

Toxins

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show abstract

“…The authors proposed that this may provide a link between BMAA and the PDC symptom of pigmentary retinopathy [ 80 ]. Also in 2009, Lopicic et al [ 81 ] showed that 1 mM BMAA (with 20 mM bicarbonate) causes in vitro membrane potential depolarization of leech nerve cells by action on non-NMDA ionotropic glutamate receptors. A concomitant increase in cell membrane input conductance, as well as an increase in Na + activity and a decrease in K + activity was noted.…”

Section: Summary Of the Multiple Mechanisms Of Bmaa Activitymentioning

confidence: 99%

“…The physiological concentrations of bicarbonate ions (10 mM and above) reacts with BMAA to form a β-carbamate [ 60 ]. In this form, BMAA can compete in binding various glutamate receptors, such as NMDA receptors [ 55 , 56 , 64 , 65 ], AMPA receptors [ 55 , 56 ], and metabotropic and ionotropic glutamate receptors [ 65 , 73 , 81 , 84 ] ( Figure 3i ). Activation of the various glutamate receptors leads to shifts in cellular ion concentrations resulting in increases in Na + [ 81 ] and Ca 2+ [ 70 , 76 , 84 ], and a decrease in K + [ 81 ] concentrations ( Figure 3ii ).…”

Section: A Summary Of the Mode Of Action Of Bmaa Based On The Currmentioning

confidence: 99%

“…In this form, BMAA can compete in binding various glutamate receptors, such as NMDA receptors [ 55 , 56 , 64 , 65 ], AMPA receptors [ 55 , 56 ], and metabotropic and ionotropic glutamate receptors [ 65 , 73 , 81 , 84 ] ( Figure 3i ). Activation of the various glutamate receptors leads to shifts in cellular ion concentrations resulting in increases in Na + [ 81 ] and Ca 2+ [ 70 , 76 , 84 ], and a decrease in K + [ 81 ] concentrations ( Figure 3ii ). Activation also causes the cell to become depolarised [ 73 ] leading to permeabilisation of the cell membrane, resulting in the release of noradrenalin [ 64 ] ( Figure 3iii ).…”

Section: A Summary Of the Mode Of Action Of Bmaa Based On The Currmentioning

confidence: 99%

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Does α-Amino-β-methylaminopropionic Acid (BMAA) Play a Role in Neurodegeneration?

Chiu

Gehringer

Welch

et al. 2011

IJERPH

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The association of α-amino-β-methylaminopropionic acid (BMAA) with elevated incidence of amyotrophic lateral sclerosis/Parkinson’s disease complex (ALS/PDC) was first identified on the island of Guam. BMAA has been shown to be produced across the cyanobacterial order and its detection has been reported in a variety of aquatic and terrestrial environments worldwide, suggesting that it is ubiquitous. Various in vivo studies on rats, mice, chicks and monkeys have shown that it can cause neurodegenerative symptoms such as ataxia and convulsions. Zebrafish research has also shown disruption to neural development after BMAA exposure. In vitro studies on mice, rats and leeches have shown that BMAA acts predominantly on motor neurons. Observed increases in the generation of reactive oxygen species (ROS) and Ca2+ influx, coupled with disruption to mitochondrial activity and general neuronal death, indicate that the main mode of activity is via excitotoxic mechanisms. The current review pertaining to the neurotoxicity of BMAA clearly demonstrates its ability to adversely affect neural tissues, and implicates it as a potentially significant compound in the aetiology of neurodegenerative disease. When considering the potential adverse health effects upon exposure to this compound, further research to better understand the modes of toxicity of BMAA and the environmental exposure limits is essential.

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“…To date, BMAA is known to cross the blood-brain barrier (BBB) [ 23 ] and exert neurotoxicity through competitive binding to various glutamate receptors namely NMDA and AMPA receptors [ 24 ]. BMAA activates glutamate receptors and shifts cellular ionic enrichment resulting in an increase in Na + [ 25 ] and Ca 2+ [ 26 ] and decrease in K + concentrations [ 25 ]. Increased Ca 2+ disrupts normal mitochondrial function leading to ROS overproduction and cytochrome c release into the cytosol, which initiates apoptosis [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer’s disease features in cortical neurons

Silva

Candeias

Esteves

et al. 2020

J Neuroinflammation

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Background After decades of research recognizing it as a complex multifactorial disorder, sporadic Alzheimer’s disease (sAD) still has no known etiology. Adding to the myriad of different pathways involved, bacterial neurotoxins are assuming greater importance in the etiology and/or progression of sAD. β-N-Methylamino-l-alanine (BMAA), a neurotoxin produced by some microorganisms namely cyanobacteria, was previously detected in the brains of AD patients. Indeed, the consumption of BMAA-enriched foods has been proposed to induce amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), which implicated this microbial metabolite in neurodegeneration mechanisms. Methods Freshly isolated mitochondria from C57BL/6 mice were treated with BMAA and O2 consumption rates were determined. O2 consumption and glycolysis rates were also measured in mouse primary cortical neuronal cultures. Further, mitochondrial membrane potential and ROS production were evaluated by fluorimetry and the integrity of mitochondrial network was examined by immunofluorescence. Finally, the ability of BMAA to activate neuronal innate immunity was quantified by addressing TLRs (Toll-like receptors) expression, p65 NF-κB translocation into the nucleus, increased expression of NLRP3 (Nod-like receptor 3), and pro-IL-1β. Caspase-1 activity was evaluated using a colorimetric substrate and mature IL-1β levels were also determined by ELISA. Results Treatment with BMAA reduced O2 consumption rates in both isolated mitochondria and in primary cortical cultures, with additional reduced glycolytic rates, decrease mitochondrial potential and increased ROS production. The mitochondrial network was found to be fragmented, which resulted in cardiolipin exposure that stimulated inflammasome NLRP3, reinforced by decreased mitochondrial turnover, as indicated by increased p62 levels. BMAA treatment also activated neuronal extracellular TLR4 and intracellular TLR3, inducing p65 NF-κB translocation into the nucleus and activating the transcription of NLRP3 and pro-IL-1β. Increased caspase-1 activity resulted in elevated levels of mature IL-1β. These alterations in mitochondrial metabolism and inflammation increased Tau phosphorylation and Aβ peptides production, two hallmarks of AD. Conclusions Here we propose a unifying mechanism for AD neurodegeneration in which a microbial toxin can induce mitochondrial dysfunction and activate neuronal innate immunity, which ultimately results in Tau and Aβ pathology. Our data show that neurons, alone, can mount inflammatory responses, a role previously attributed exclusively to glial cells.

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Augmentation and ionic mechanism of effect of β-N-methylamino-l-alanine in presence of bicarbonate on membrane potential of Retzius nerve cells of the leech Haemopis sanguisuga

Cited by 19 publications

References 40 publications

Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy

Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy

Does α-Amino-β-methylaminopropionic Acid (BMAA) Play a Role in Neurodegeneration?

Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer’s disease features in cortical neurons

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