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Int. J. Environ. Res. Public Health 2011, 8(9), 3728-3746; doi:10.3390/ijerph8093728

Does α-Amino-β-methylaminopropionic Acid (BMAA) Play a Role in Neurodegeneration?
Alexander S. Chiu, Michelle M. Gehringer, Jeffrey H. Welch and Brett A. Neilan *
The School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
Author to whom correspondence should be addressed; Tel.: +61-2-9385-3235; Fax: +61-2-9385-1483.
Received: 6 June 2011; in revised form: 9 September 2011 / Accepted: 9 September 2011 / Published: 16 September 2011


: 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.
BMAA; neuron; glia; neural; neurodegeneration; excitotoxicity; ALS; PDC; cycad; toxicology; cyanobacteria; Alzheimer’s; Parkinson’s

1. The Cycad Hypothesis

Medical research attention was drawn towards Guam in 1953 when it was reported that the incidence of an amyotrophic lateral sclerosis/Parkinson’s disease complex (ALS/PDC) within the local Chamorro people was 100 times higher than the rest of the world [13]. After failing to identify any clear genetic correlation to this observation, attention was turned to environmental/cultural factors that might be responsible [2,3]. The use of cycad (Cycas circinalis) flour to make tortillas, soups and dumplings by the native Chamorro people [4,5], coupled with various field reports that livestock developed progressive and irreversible ataxia after ingesting cycads [6], led to the suggestion that cycad consumption could be the cause of the human condition [5], and thus the cycad hypothesis was born. In 2007 a group of biostatisticians, led by Borenstein, conducted an in depth population study of the Chamorro people, statistically showing that eating cycads presented the highest associated risk of developing ALS/PDC [7].

3. Neurodegeneration is Caused by Excitotoxicity

Excitatory amino acids (EAAs) act as neurotransmitters within the nervous system [42]. Their action is performed by binding to EAA receptors that are present on all nerve cells, particularly concentrated in the synapses. EAA receptors mediate excitatory synaptic transmission via control of the flow of ions, most notably Ca2+, K+, Na+, Mg2+ and Cl [43]. Malfunctions in this system can lead to neurons being damaged and fatally compromised, a process known as excitotoxicity [44]. Excitotoxic cell death involves prolonged depolarization of neurons, changes in intracellular calcium concentrations, and the activation of enzymatic and nuclear mechanisms of cell death [45]. The main EAA receptors are quisqualate/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-apartate (NMDA) and metabolic glutamate receptors (mGluR), all of which are activated by glutamate and similar substances. A review by Doble [45] explained all these concepts and activities in great detail. The idea that excitotoxicity is a main player in neurodegenerative disease is supported by many studies that have shown that there is an increased level of glutamate found in the cerebrospinal fluid of ALS patients [4650].

4. Summary of the Multiple Mechanisms of BMAA Activity

With substantial and ever growing evidence that BMAA does play a role in the onset and progression of neurodegenerative diseases, the most important question is; what mode of activity does BMAA exert? Although BMAA had not yet been discovered, Dastur [51] fed cycad flour pancakes to Rhesus monkeys in 1964, observing various effects including muscle atrophy and neurodegeneration. Although given that cycad flour was used rather than pure BMAA, these effects may have potentially been influenced by other compounds present in the mixture. Immediately following the discovery of BMAA in 1967, Bell et al. [52,53] also conducted some very basic toxicity assays by intraperitoneally injecting BMAA into chicks and rats and observing the development of neurological symptoms via impairment of normal physical function in both cases. These findings were repeated in 1972 by Polsky et al. [54], with addition of mice as test subjects. In all cases all the animals suffered the same symptoms, namely weakness, convulsions and general lack of coordination. After this study no productive research using BMAA was conducted until 1987, when the revolutionary investigation of Spencer et al. [13] was reported. In those studies macaques were fed 100–350 mg/kg BMAA daily for up to thirteen weeks, resulting in corticomotoneuronal dysfunction, Parkinsonian features and behavioural abnormalities. The 1991 study of Rakonczay et al. [55] and 1993 study of Matsuoka et al. [56] produced similar findings, with BMAA injected rats displaying acute physical impairment including poor balance, poor coordination and convulsions. Contrary to these observations, the 1989 study of Perry et al. [57] fed high doses of BMAA (15.5 g/kg total, 500 mg/kg or 1000 mg/kg doses) to mice over an 11 week period, and observed no behavioural abnormalities during the course of the experiment. Analysis of brain and liver samples collected post euthanasia failed to find any evidence of neurochemical or neuropathological changes in the any of the sample animals [57]. Similarly, in 2006 the group of Cruz-Aguado et al. [58] fed 28 mg/kg of BMAA, which was an exposure level they deemed to be an accurate environmental representation, to mice daily for 30 days. In this study they found no indication that neurological damage had occurred [58]. In the critical review by Karamyan and Speth [31], the authors raise doubts over the methods used by Perry et al. [57] to observe behavioural differences, and over the doses used by Cruz-Aguado et al. [58], as possible explanations for their negative observations. It was also suggested by Banack et al. [59] that the mouse model may be a poor model to demonstrate the neurotoxicity of BMAA. It is evident that the bulk of early research was focused on either detecting BMAA in known (deceased) neurodegenerative sufferers, or observing behavioural changes in lab animals fed or injected with BMAA. While this information was useful it did nothing to explain the actual mechanisms of BMAA activity.

The first mechanistic BMAA research was performed in 1988 when Weiss and Choi [60] discovered that BMAA only displayed activity in vitro when a physiological concentration (10 mM and above) of bicarbonate (HCO3) ions were present in the media. This discovery was soon followed by Richter and Mena’s [61] observation that BMAA inhibited glutamate binding in the synaptic junctions of rat brains at 1 mM, but only in the presence of 20–25 mM bicarbonate ions. The observation that effective inhibition of glutamate receptors was not achieved by BMAA at the extremely high level of 10 mM, independent of bicarbonate ions, supported the findings of Weiss and Choi [60], that HCO3 was required for BMAA activity to occur. Follow up experiments showed that BMAA could bind to NMDA and non-NMDA receptors on mouse cortical neurons [62]. The dependence of BMAA on HCO3 was a critical discovery as it greatly affected the results of experiments conducted using freshly isolated tissues where experimental reagents are generally simple and defined, and often did not contain HCO3. Using these leads Myers and Nelson [63] identified a β-carbamate of BMAA (formed in the presence of bicarbonate), that shares structural characteristics with glutamic acid (glutamate, see Figure 2). This led to an explanation of a mechanism of activity, as it suggested that BMAA may have the ability to inhibit glutamate receptors. From this point on all researchers used media and/or buffers supplemented with a minimum of 20 mM bicarbonate in all active in vitro assays.

In 1990 Lindström et al. [64] gave intracerebral injections (10 or 400 μg) of BMAA to mice and after one week they noticed a decrease in noradrenalin (NA) levels in the hypothalamus, while there was no effect on dopamine or serotonin levels. No physical or behavioural effects were observed in the exposed animals. They suggested that the decrease in NA levels in the tissue may have been the result of BMAA activity on NMDA receptors, causing a release of NA. Copani et al. [65] conducted a thorough investigation of BMAA binding capabilities and specificities by performing in vitro assays. Brain slices and mixed primary cultures taken from 8-day old rats were exposed to BMAA at 1 mM in conjunction with various neural metabolites and antagonists of NMDA. Their results indicated that BMAA acts as a mixed agonist of metabotropic and NMDA receptors, and as seen in other studies, BMAA activity was enhanced by the presence of bicarbonate ions at 25 mM [65]. The groups of Rakonczay et al. [55] and Matsuoka et al. [56] performed a series of binding assays using various receptor antagonists after giving intracerebroventricular injections of BMAA (500 μg/day, for up to 60 days) to rats. Their results indicated that BMAA has a mixed agonistic effect on EAA, NMDA and quisqualate/AMPA receptors in the synapse. In 1991–1992 Duncan’s research group conducted a number of experiments relating to the body’s ability to take up BMAA after oral exposure and transport and accumulate it in the brain. When cynomologous monkeys were orally dosed with BMAA, a maximum of 20% of the administered dose was metabolized, and no greater than 2.1% was excreted indicating that approximately 80% of orally consumed BMAA was absorbed into systemic circulation [66]. The 1998 study by Kisby et al. [67] reported that BMAA was detected in the cerebrospinal fluid of orally dosed monkeys, and in the brain tissue of intraperitoneally dosed rats, suggesting that BMAA is able to cross the blood-brain barrier. In a later study, Duncan et al. [68] demonstrated in rats that, after intravenous injection, acute BMAA levels in the brain peaked at eight h post administration. They also demonstrated that BMAA is taken up into the brain by the large neutral amino acid carrier of the blood-brain barrier, which suggests that uptake may be sensitive to the same factors that affect neutral amino acid transport such as diet, metabolism, disease and age [69]. In essence this means that BMAA uptake into the brain may be increased in times of stress.

Brownson et al. [70] assayed rat brain cells for changes in the concentration of Ca2+ in the presence of BMAA (5 mM) with or without HCO3 ions. This experiment indicated that there was a small increase in intracellular Ca2+ concentration with BMAA only, but a large increase when BMAA and HCO3 were added together. This further supports the belief that BMAA is dependant on HCO3 as a cofactor and that the correspnding β-carbamate is the active compound. It also suggests another potential mechanism of activity as impairment to intracellular calcium homeostasis has been shown to cause disruptions in Ca2+-dependant cascades that lead to neuronal cell death and neurodiseases [71,72].

The study of Nedeljkov et al. [73] measured the membrane input resistance of the nerve cells of the leech Haemopis sanguisuga after treatment with BMAA (100 μM–10 mM) and HCO3 (20 mM). A significant reduction in input membrane resistance was measured, indicating that BMAA depolarizes the cell by increasing membrane permeability and conductance.

In 2007, Buenz and Howe [74] intracranially injected 10 μL of 100 mM BMAA into mice that were then euthanized at 24 h post exposure. This study showed that BMAA caused injury to hippocampal neurons. They also demonstrated that BMAA increasingly caused a degree of cell death in NSC-34 cells (a mouse derived spinal motor neuron-like cell line) as the amount of BMAA administered increased from 100 μM up to 1 mM. A study conducted by Lobner et al. in 2007 [75] showed that BMAA at concentrations as low as 10 μM can potentiate neuronal injury caused by other known neurotoxins such as amyloid-β and MPP+. This observation holds great significance determining that very low concentrations of BMAA (orders of magnitude lower than previously thought) can potentially cause serious neurological damage if other factors are involved. This study also showed that BMAA has three-fold activity by causing excitotoxicity on NMDA and metabotropic glutamate receptor subtype 5 (mGluR5) receptors, and via oxidative stress. This supports the notion that BMAA may play a role in a variety of different neurodegenerative conditions. Rao et al. [76] concluded that low concentrations of BMAA (30 μM) selectively injure motor neurons via excitotoxic activation of AMPA/kainite receptors. They also showed that BMAA induces increases in Ca2+ concentrations and the generation of selective reactive oxygen species (ROS) in motor neurons, with minimal effect on other spinal neurons. Liu et al. [77] validated the three-fold activity of BMAA described by Lobner et al. [75], as well as suggesting that the mechanism BMAA uses to induce oxidative stress is through inhibition of the cystine/glutamate antiporter system Xc, leading to glutathione depletion and oxidative stress [77]. In 2009, Nunn and Ponnusamy [78] found that 2,3-diaminopropionic acid, the dimethylated product of BMAA, and methylamine were formed in liver and kidney preparations from rats exposed to 10 mM BMAA for 24 h in vitro. It is worth noting that this product was not formed in brain tissues in this study. This provides evidence of yet another method of toxicity by BMAA, although the test dose is potentially too high for the result to be environmentally significant. Production of methylamine is significant as it has been shown to produce a state of oxidative stress in rats [79]. In 2009, Karlsson et al. [80] injected radioactively labelled BMAA into frogs and mice, then euthanized the animals at 30 min, 1 h, 3 h, 24 h and 12 days post injection. The results showed that BMAA interacts/binds with melanin, particularly during its synthesis, and increasingly bioaccumulates in melanin and neuromelanin-containing cells over time. 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. This indicated that, in addition to AMPA/kainite receptors, BMAA could initiate excitotoxicity through the activation of other non-NMDA ionotropic glutamate receptors. In 2009, Santucci et al. [82] injected 5–10 nM BMAA into the eyes of mice, that were then euthanized between 4 and 24 h post administration. Increases in retinal neuron death and the production of ROS were observed in this study. Also in 2009, Purdie et al. [83] exposed zebrafish embryos to BMAA at up to 50,000 μg/L (approx. 300 mu;M) for 5 days. This exposure resulted in a range of neuromuscular and developmental abnormalities, which could be directly related to disruptions to the glutamatergic signalling pathways.

In 2010, Cucchiaroni et al. [84] found rat neurons exposed to 1 or 3 mM BMAA displayed increases in the production of ROS, influx of Ca2+ and a massive release of cytochrome-c (cyt-c) into the cytosol. This study also demonstrated that activity was predominantly mediated via mGluR1 receptors. These observations indicate disruption to mitochondrial activity, excitotoxicity, and induction of apoptosis induced by exposure to BMAA. More recently Karlsson et al. [85] injected 50 and 200 mg/kg BMAA into neonatal rats and found that it inhibited neural development leading to long-term cognitive impairment and supporting the zebrafish data implicating BMAA as a developmental neurotoxin [83]. Most recently, Lee and McGeer [86] exposed three different neuronderived human cancer cell lines to BMAA. Interestingly they observed that BMAA did not cause damage to human neurons and concluded that the hypothesis of BMAA causing neurodegeneration in humans was not tenable [86]. It should however be noted, that the cell lines they used were highly proliferative immortalized cells that differ significantly in physiological characteristics from normal neurons in vivo. Summaries of both in vivo and in vitro investigations into the bioactivity of BMAA are presented in Tables 1 and 2 respectively.

When reviewing BMAA literature it quickly becomes clear that there are large differences in opinion. When Borenstein et al. [7] proposed their correlation supporting the role of cycads (potential involvement of BMAA), Steele and McGeer [87] raised doubt over the statistics. When Duncan et al. [14] indicated that greater than 80% of BMAA is removed from cycad flour during processing (washing), Cheng and Banack [88] claimed that due to sampling methods, the amount of BMAA detected by Duncan et al. [14] has been underestimated by 7- to 30-fold and based on the assumption that BMAA is washed away, another candidate compound such as β-sitosterol β-d-glucoside (BSSG) is suggested to play the same proposed role [89]. Various studies have been conducted to indicate that BSSG does display neurotoxic properties [90,91]. Interestingly despite suggestion that BMAA and BSSG are alternatives for each other, involvement of either or both, would support the same cycad hypothesis.

5. A Summary of the Mode of Action of BMAA based on the Current Literature

The studies listed in Tables 1 and 2, while executed on vastly different test models with varying measurement parameters, can be combined to generate an image of the mechanisms of action of BMAA on a primary motor neuron as illustrated in Figure 3. After being orally consumed, 80% of ingested BMAA passes from the gut into the blood stream [66]. BMAA then crosses the blood-brain barrier via large neutral amino acid carriers [68]. 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 Ca2+ [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). BMAA also inhibits the cysteine/glutamate antiporter system Xc [77] (Figure 3iv), preventing the uptake of cysteine, resulting in glutathione depletion, which contributes to increases in oxidative stress. At the same time the system Xc increases the release of glutamate from the cell (Figure 3v), which can then bind to glutamate receptors increasing damage by excitotoxicity [77] (Figure 3vi). Increases in intracellular Ca2+ concentrations disrupt normal mitochondrial function leading to the release of ROS into the cytoplasm, thereby contributing to the observed increases in ROS [75,76,82,84] (Figure 3vii). In addition, cytochrome-c is released from the mitochondria [84] (Figure 3viii) resulting in the induction of apoptosis.

6. Concluding Remarks

Whilst the incidence of ALS-PDC on Guam was 100 times that of the world average, it peaked at 120 cases per 100,000 people, meaning that the majority of individuals thought to be exposed to BMAA still escaped disease. Clearly there is still much to learn about the role(s) that BMAA plays in neurodegeneration. Karamyan and Speth have reviewed the available literature on the evidence for and against the involvement of BMAA in the development of ALS/PDC [31]. They concluded that the majority of studies indicate that BMAA is toxic. It is worth noting that the two studies [57,58] that observed no effect both utilized oral administration methods, perhaps implying reduced toxicity via this delivery method. One must also consider that the severe effects observed by Spencer et al. [13] were also obtained with oral dosing.

When considering all the published data, it appears certain that BMAA can contribute to the onset and progression of neurodegenerative disease in certain susceptible individuals. It would be useful to focus on better understanding the proposed mechanisms of BMAA activity, as well as identifying new as yet undescribed mechanisms that might play an important role in the overall potency of BMAA. Without a sound understanding of how BMAA truly works, it is impossible to predict the level of risk it poses with any significant degree of confidence. One question posed in the review by Karamyan and Speth [31] that is likely to be answered in the affirmative was “are there interactions between BMAA and other exogenous substances with possible synergetic toxicity?”. The potential dangers of BMAA acting as an accessory or combinatorial toxin, rather than being highly toxic as a sole entity, were indicated by Lobner et al. [75] when they demonstrated that BMAA can potentiate the activity of other insults. As BMAA has been shown to be co-present with other cyanotoxins, such as microcystin, anatoxin-a, nodularin and saxitoxin [92], this potentiation capability, may implicate BMAA as an important factor when considering the management strategies of these other toxins. The debate between BSSG and BMAA appears to be very polarized, with acceptance of one causative agent completely ruling out the significance of the other. It may however be more logical to consider the idea that as the two compounds were isolated from the same source, they are likely to be present together environmentally, and could therefore act in a combination, potentially far more potent than either agent alone, to induce neurological damage. There is little doubt that if present in sufficient concentrations, BMAA exerts multiple modes of neurotoxic activity, with perhaps further modes yet to be defined. With growing reports of its presence in varied environments it is important that research to understand the complete nature of BMAA toxicity continue. Equipped with a greater knowledge and understanding of the mechanisms of BMAA toxicity, we will be able to more accurately evaluate and assess the human health risks posed by exposure to this cyanotoxin.

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Figure 1. The chemical structure of β-methylaminoalanine (BMAA).
Figure 1. The chemical structure of β-methylaminoalanine (BMAA).
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Figure 2. Comparison of the structure of (A) β-carbamate (BMAA adduct) and (B) glutamtic acid (glutamate).
Figure 2. Comparison of the structure of (A) β-carbamate (BMAA adduct) and (B) glutamtic acid (glutamate).
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Figure 3. Illustrative summary of the modes of action of BMAA on neurons. In vivo, BMAA is present as a β-carbamate (represented by the blue dots), which binds to NMDA, AMPA and mGlu receptors (i). Activation of glutamate receptors results in an increase in the levels of Na+ and Ca2+ in the cell, accompanied by a reduction in K+ (ii). The cell becomes depolarised and the membrane becomes permeable, as illustrated by the dotted line, and combined with NMDA receptor activity, noradrenalin is released from the cell as a result (iii). The cysteine/glutamate antiporter system Xc is inhibited, as indicated by the red X (iv), leading to intracellular depletion of glutathione and an increase in ROS. This inhibition also causes an increase in the release of glutamate (v), which then binds to receptors to induce further excitotoxicity (vi). All these mechanisms combine to cause an increase in the generation of ROS (vii). The elevation of Ca2+ leads to overload of the mitochondria resulting in a massive release of cyt-c into the cytosol (viii).
Figure 3. Illustrative summary of the modes of action of BMAA on neurons. In vivo, BMAA is present as a β-carbamate (represented by the blue dots), which binds to NMDA, AMPA and mGlu receptors (i). Activation of glutamate receptors results in an increase in the levels of Na+ and Ca2+ in the cell, accompanied by a reduction in K+ (ii). The cell becomes depolarised and the membrane becomes permeable, as illustrated by the dotted line, and combined with NMDA receptor activity, noradrenalin is released from the cell as a result (iii). The cysteine/glutamate antiporter system Xc is inhibited, as indicated by the red X (iv), leading to intracellular depletion of glutathione and an increase in ROS. This inhibition also causes an increase in the release of glutamate (v), which then binds to receptors to induce further excitotoxicity (vi). All these mechanisms combine to cause an increase in the generation of ROS (vii). The elevation of Ca2+ leads to overload of the mitochondria resulting in a massive release of cyt-c into the cytosol (viii).
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Table 1. A chronological summary of mechanisms of BMAA activity determined by in vivo research.
Table 1. A chronological summary of mechanisms of BMAA activity determined by in vivo research.
Routez of exposureSpeciesDose level, exposure timeResearch group and dateObservations
Intraperitoneal injectionsRat
6–14 μmoles/g body weight
3–7 μmoles/g body weight
Vega and Bell. 1967Weakness, convulsions and uncoordination
Intraperitoneal injectionsRat
6–14 μmoles/g body weight
3–7 μmoles/g body weight
6–14 μmoles/g body weight
Polski et al. 1972Weakness, convulsions and uncoordination
Perorally Intraperitoneal injectionsMonkey
100–350 mg/kg, 12 months
500 mg/kg daily, 14 days
Kisby et al. 1988BMAA can cross from gut to blood
BMAA can cross the blood brain barrier
GavageMonkey100–350 mg/kg daily, up to 10 weeksSpencer et al. 1987Corticomotoneuronal dysfunction, Parkinsonian features and behavioural abnormalities
GavageCynomologous monkey500 mg/kg daily, 18 days, then
500 mg/kg 2 daily, 28 days, then
100mg/kg 2 daily, 30 days
Perry et al. 1989No behavioral or physiological effects observed
Intracerebral injectionsRat10 μg or 400 μg/150–200 g ratLindström et al. 1990Activation of NMDA receptor, release noradrenalin from cells
Intracerebroventricular injectionsRat500 μg/day
200–250 g body weight, 10–60 days
Rakonczay et al. 1990
Matsuoka et al. 1993
Agonistic effects on NMDA, EAA and AMPA receptors in synapse Physical impairment. Mixed agonistic receptor activity
Gavage and intravenous injectionsCynomologous monkey, rat2 mg/kg gavage; 1 mg/kg iv
100 mg/kg gavage; 24–400 mg/kg iv
Duncan et al. 1991–199280% of ingested BMAA enters systemic circulation. BMAA can cross the blood brain barrier.
BMAA is transported by neutral amino acid carriers so uptake can be influenced by diet, metabolism, disease and age
Dosed feed pelletsMouse28 mg/kg daily, 30 daysCruz-Aguado et al. 2006No motor, cognitive or neuropathological effect observed
Intracranial injectionsMouse10 μL of 100 mM, 24 hBuenz and Howe. 2007Injury to hippocampal neurons
Intravenous and subcutaneous injectionsMouse and frog7.3 μg/kg, 30 min, 1 h, 3 h, 24 h, 12 daysKarlsson et al. 2009BMAA interacts/binds melanin, particularly during synthesis, and accumulates in melanin and neuromelanin containing cells increasingly over time
Ocular injectionsMouse5–10 nmol, 4, 8 and 24 hSantucci et al. 2009Retinal neuron death and production of ROS
Table 2. A chronological summary of mechanisms of BMAA activity determined by in vitro research.
Table 2. A chronological summary of mechanisms of BMAA activity determined by in vitro research.
Experimental modelSpeciesDose level, exposure timeResearch group and dateConclusion
Primary cortical neuronsMouse3 mM, 1 h With and without 10–24 mM HCO3Weiss and Choi, 1988BMAA activity is dependent on bicarbonate at a min. of 20mM
Primary cortical neuronsMouse300 μM–3 mM, 24 hWeiss et al. 1989BMAA has activity on NMDA and non-NMDA receptors
Primary cortical neuronsRat1 mMRichter and Mena, 1989Inhibition of glutamate binding in synapse, impaired neuron function
Chemical assay-Myers and Nelson, 1990Formation of bicarbonate adduct with structural similarity to glutamate
Brain slicesRat1 mM, acuteCopani et al. 1991BMAA acts as a mixed agonist of metabotropic and NMDA receptors
Minced brainRat5 mM, acuteBrownson et al. 2002Impairment of intracellular calcium ion homeostasis.
Possible neuronal death. Effects on calcium dependent cascades
Primary nerve cellsLeech1–10 mM, acuteNedeljkov et al. 2005Depolarisation of cell, impaired nerve function.
Membrane permeabilisation. Activity via glutamate receptors
Primary embryonic spinal cord cultureMouse30–1000 μM, 20–24 hRao et al. 2006Increase on calcium ion concentration and ROS.
Selective damage to motor neurons
Primary mixed cortical cellsMouse0.1–10 mM, 24 h 3 mM, 3 h (DCFDA)Lobner et al. 2007Potentiation of other insults, makes cells more sensitive to other compounds. Increase in ROS
NSC-34 cellsMouse50–1000 μM, 18 hBuenz and Howe 2007Dose dependent death of NSC-34 cells
Primary mixed cortical cell culturesMouse3 mM, 3 hLiu et al. 2009Induction of oxidative stress is through inhibition of the cystine/glutamate antiporter system Xc
Brain slices. Brain, liver, kidney homogenatesRat10 mM, 30 min for slices
1 h for homogenates
Nunn and Ponnusamy, 2009The dimethylated product of BMAA, 2,3-diaminopropionic acid was formed in liver and kidney (but not brain) preparations
Nerve cellsLeech100–3000 μM, acuteLopicic et al. 2009Action on non-NMDA ionotropic glutamate receptors, with a concomitant increase in cell membrane input conductance, as well as an increase in Na+ activity and a decrease in K+ activity.
Possible initiation of excitotoxicity through activation of non-NMDA ionotropic glutamate receptors
Brain slicesRat100–10000 μM, acuteCucchiaroni et al. 2010BMAA activates mGluR1 receptors to cause neuronal degeneration
Massive release of cyt-c into cytosol
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