Perinatal Exposure to the Cyanotoxin β-N-Méthylamino-l-Alanine (BMAA) Results in Long-Lasting Behavioral Changes in Offspring—Potential Involvement of DNA Damage and Oxidative Stress
Abstract:We recently demonstrated that perinatal exposure to the glutamate-related herbicide, glufosinate ammonium, has deleterious effects on neural stem cell (NSC) homeostasis within the sub-ventricular zone (SVZ), probably leading to ASD-like symptoms in offspring later in life. In the present study, we aimed to investigate whether perinatal exposure to another glutamate-related toxicant, the cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA), might also trigger neurodevelopmental disturbances. With this aim… Show more
“…It is a common neurotoxin utilized in the study of neurodegeneration in cellular and animal models, specifically those for the study of ALS/Parkinsonism-dementia complex. BMAA causes neuroinflammation, oxidative stress, apoptosis and cognitive impairment (Brownson et al, 2002; Lobner, 2009; Santucci et al, 2009; Zhou et al, 2010; Muñoz-Saez et al, 2013; Al-Sammak et al, 2015; Takser et al, 2016; Laugeray et al, 2017; Petrozziello et al, 2017). It elicits neurotoxicity by acting as an agonist for glutamate receptors such as AMPARs/KARs, NMDARs, and mGluR5 (Lobner, 2009; Delzor et al, 2014).…”
Section: Glutamate Receptors As Potential Targets In Neurotoxic Agentmentioning
Glutamate receptors play a crucial role in the central nervous system and are implicated in different brain disorders. They play a significant role in the pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Although many studies on NDDs have been conducted, their exact pathophysiological characteristics are still not fully understood. In in vivo and in vitro models of neurotoxic-induced NDDs, neurotoxic agents are used to induce several neuronal injuries for the purpose of correlating them with the pathological characteristics of NDDs. Moreover, therapeutic drugs might be discovered based on the studies employing these models. In NDD models, different neurotoxic agents, namely, kainic acid, domoic acid, glutamate, β-N-Methylamino-L-alanine, amyloid beta, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridinium, rotenone, 3-Nitropropionic acid and methamphetamine can potently impair both ionotropic and metabotropic glutamate receptors, leading to the progression of toxicity. Many other neurotoxic agents mainly affect the functions of ionotropic glutamate receptors. We discuss particular neurotoxic agents that can act upon glutamate receptors so as to effectively mimic NDDs. The correlation of neurotoxic agent-induced disease characteristics with glutamate receptors would aid the discovery and development of therapeutic drugs for NDDs.
“…It is a common neurotoxin utilized in the study of neurodegeneration in cellular and animal models, specifically those for the study of ALS/Parkinsonism-dementia complex. BMAA causes neuroinflammation, oxidative stress, apoptosis and cognitive impairment (Brownson et al, 2002; Lobner, 2009; Santucci et al, 2009; Zhou et al, 2010; Muñoz-Saez et al, 2013; Al-Sammak et al, 2015; Takser et al, 2016; Laugeray et al, 2017; Petrozziello et al, 2017). It elicits neurotoxicity by acting as an agonist for glutamate receptors such as AMPARs/KARs, NMDARs, and mGluR5 (Lobner, 2009; Delzor et al, 2014).…”
Section: Glutamate Receptors As Potential Targets In Neurotoxic Agentmentioning
Glutamate receptors play a crucial role in the central nervous system and are implicated in different brain disorders. They play a significant role in the pathogenesis of neurodegenerative diseases (NDDs) such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Although many studies on NDDs have been conducted, their exact pathophysiological characteristics are still not fully understood. In in vivo and in vitro models of neurotoxic-induced NDDs, neurotoxic agents are used to induce several neuronal injuries for the purpose of correlating them with the pathological characteristics of NDDs. Moreover, therapeutic drugs might be discovered based on the studies employing these models. In NDD models, different neurotoxic agents, namely, kainic acid, domoic acid, glutamate, β-N-Methylamino-L-alanine, amyloid beta, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridinium, rotenone, 3-Nitropropionic acid and methamphetamine can potently impair both ionotropic and metabotropic glutamate receptors, leading to the progression of toxicity. Many other neurotoxic agents mainly affect the functions of ionotropic glutamate receptors. We discuss particular neurotoxic agents that can act upon glutamate receptors so as to effectively mimic NDDs. The correlation of neurotoxic agent-induced disease characteristics with glutamate receptors would aid the discovery and development of therapeutic drugs for NDDs.
“…It is widely accepted that the developing brain is more sensitive to the harmful effects of environmental contaminants than the adult brain 36 . It is important to mechanistically elucidate BMAA's effects on the developing brain, as this toxin has been detected in water and food chains all over the world 37–39 , and is shown to adversely affect the immature brain 25,27,40–42 . The present study revealed different susceptibilities of primary striatal neurons and NSC to BMAA-induced toxicity.…”
The widespread environmental contaminant β-methylamino-L-alanine (BMAA) is a developmental neurotoxicant that can induce long-term learning and memory deficits. Studies have shown high transplacental transfer of 3H-BMAA and a significant uptake in fetal brain. Therefore, more information on how BMAA may influence growth and differentiation of neural stem cells is required for assessment of the risk to the developing brain. The aim of this study was to investigate direct and mitotically inherited effects of BMAA exposure using primary striatal neurons and embryonic neural stem cells. The neural stem cells were shown to be clearly more susceptible to BMAA exposure than primary neurons. Exposure to 250 µM BMAA reduced neural stem cell proliferation through apoptosis and G2/M arrest. At lower concentrations (50–100 µM), not affecting cell proliferation, BMAA reduced the differentiation of neural stem cells into astrocytes, oligodendrocytes, and neurons through glutamatergic mechanisms. Neurons that were derived from the BMAA-treated neuronal stem cells demonstrated morphological alterations including reduced neurite length, and decreased number of processes and branches per cell. Interestingly, the BMAA-induced changes were mitotically heritable to daughter cells. The results suggest that early-life exposure to BMAA impairs neuronal stem cell programming, which is vital for development of the nervous system and may result in long-term consequences predisposing for both neurodevelopmental disorders and neurodegenerative disease later in life. More attention should be given to the potential adverse effects of BMAA exposure on brain development.
“…The inflammatory environment in ALS changes with disease progression. Resident glial cells and infiltrating immune cells are considered among the major producers of ROS and reactive nitrogen species, which contribute to the pathological conditions of the CNS, including phagocytosis and apoptosis of the spinal cord motor neurons and neurons in the dentate gyrus (DG) region of the hippocampus [6,8,29]. The Alzheimer’s disease-like pathology is synergistic and dependent on oxidative stress and inflammation; thus, administration of anti-inflammatory agents might alleviate the disease outcome [30].…”
Amyotrophic lateral sclerosis (ALS) is an adult disorder of neurodegeneration that manifests as the destruction of upper and lower motor neurons. Beta-N-methylamino-L-alanine (L-BMAA), an amino acid not present in proteins, was found to cause intraneuronal protein misfolding and to induce ALS/Parkinsonism dementia complex (PDC), which presents symptoms analogous to those of Alzheimer’s-like dementia and Parkinsonism. L-serine suppresses the erroneous incorporation of L-BMAA into proteins in the human nervous system. In this study, angiopoietin-1, an endothelial growth factor crucial for vascular development and angiogenesis, and the integrin αvβ3 binding peptide C16, which inhibits inflammatory cell infiltration, were utilized to improve the local microenvironment within the central nervous system of an ALS/PDC rodent model by minimizing inflammation. Our results revealed that L-serine application yielded better effects than C16+ angiopoietin-1 treatment alone for alleviating apoptotic and autophagic changes and improving cognition and electrophysiological dysfunction, but not for improving the inflammatory micro-environment in the central nerve system, while further advances in attenuating the functional disability and pathological impairment induced by L-BMAA could be achieved by co-treatment with C16 and angiopoietin-1 in addition to L-serine. Therefore, C16+ angiopoietin-1 could be beneficial as a supplement to promote the effects of L-serine treatment.
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