Acuteβ-N-Methylamino-L-alanine Toxicity in a Mouse Model

Abstract

The cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) is considered to be an “excitotoxin,” and its suggested mechanism of action is killing neurons. Long-term exposure to L-BMAA is believed to lead to neurodegenerative diseases including Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis (Lou Gehrig's disease). Objectives of this study were to determine the presumptive median lethal dose (LD50), the Lowest-Observed-Adverse-Effect Level (LOAEL), and histopathologic lesions caused by the naturally occurring BMAA isomer, L-BMAA, in mice. Seventy NIH Swiss Outbred mice (35 male and 35 female) were used. Treatment group mice were injected intraperitoneally with 0.03, 0.3, 1, 2, and 3 mg/g body weight L-BMAA, respectively, and control mice were sham-injected. The presumptive LD50 of L-BMAA was 3 mg/g BW and the LOAEL was 2 mg/g BW. There were no histopathologic lesions in brain, liver, heart, kidney, lung, or spleen in any of the mice during the 14-day study. L-BMAA was detected in brains and livers in all of treated mice but not in control mice. Males injected with 0.03 mg/g BW, 0.3 mg/g BW, and 3.0 mg/g BW L-BMAA showed consistently higher concentrations (P < 0.01) in brain and liver samples as compared to females in those respective groups.

Neuro‐ and hepatic toxicological profile of (S)‐2,4‐diaminobutanoic acid in embryonic, adolescent and adult zebrafish

“…DABA is a noncanonical amino acid structurally related to ornithine and lysine in that is has a side‐chain nitrogen (Figure ). It is produced by cyanobacteria alongside β‐ N ‐methylamino‐ l ‐alanine (BMAA) (Al‐Sammak, Hoagland, Cassada, & Snow, ; Fan, Qiu, Fan, & Li, ), a well‐known neurotoxin (Al‐Sammak, Rogers, & Hoagland, ; Cox et al, ; Cox, Davis, Mash, Metcalf, & Banack, ). As this is the major biological source of DABA and as DABA is always coexpressed with the highly toxic BMAA, determining the toxicity of DABA has not been a high priority.…”

Glyphosate pathways to modern diseases VI: Prions, amyloidoses and autoimmune neurological diseases

“…BMAA has, in fact, been linked to several neurodegenerative diseases, including Parkinson's, Alzheimer's and amyotrophic lateral sclerosis (ALS) [75]. A 2013 study linked an ALS cluster in Chesapeake Bay to consumption of BMAA-contaminated crabs [76].…”

A Single Neonatal Exposure to BMAA in a Rat Model Produces Neuropathology Consistent with Neurodegenerative Diseases

“…Lindstrom et al [ 31 ], while unable to demonstrate clinical signs of neurological abnormalities, observed abundant gliosis and pyknotic neurons surrounding the BMAA injection site as well as a dose-dependent loss of tyrosine hydroxylase (TH)-immunoreactive neurons and dendrites in the lesioned areas one week following intranigral or intracisternal injections of 10 μg or 400 μg BMAA to adult rats. However, although Al-Sammak et al [ 18 ] observed clinical symptoms in adult mice, such as myoclonus, convulsions, dragging gait, shaking and ataxia, following exposure to 2000 mg/kg body weight BMAA, and subsequently detected BMAA in the brain and liver tissue of all treated animals, histopathological examination of relevant brain tissue showed no histopathologic lesions in the brain. The livers, hearts, kidneys, lungs, and spleen tissue of BMAA-exposed animals were similarly unaffected.…”

“…Although some clinical signs of BMAA toxicity have been shown in chicks, rats and mice [ 9 , 18 , 19 , 20 , 21 , 22 , 23 ] with symptoms such as convulsions and ataxia being reported at high doses (4000 mg per kilogram body weight) [ 21 ], no animal model of BMAA toxicity has successfully reproduced all the neuropathological changes that are typically seen in AD, PD and/or ALS patients. Neither Polsky et al [ 24 ], nor Perry et al [ 25 ], nor Duncan et al [ 26 ] nor Cruz-Aguado et al [ 27 ] observed any clinical signs of toxicity, or biochemical or neuropathological abnormalities associated with the administration of BMAA to adult rats.…”

“…The livers, hearts, kidneys, lungs, and spleen tissue of BMAA-exposed animals were similarly unaffected. Since the brain tissue of symptomatic mice had no histopathological deficits, Al-Sammak et al [ 18 ] suggested that BMAA might elicit its effect by causing biochemical changes rather than causing histopathologic lesions in the brain, although how this might occur is not clear. Additionally, no neuropathology was observed in rats injected subcutaneously with 200 mg/kg body weight BMAA on PND10 and mild neuronal loss could be seen only in the hippocampus of rats exposed to 600 mg/kg body weight BMAA on PND9 and 10 [ 22 , 23 , 32 ].…”