β-N-Methylamino-L-alanine (BMAA) Toxicity Is Gender and Exposure-Age Dependent in Rats

Abstract

Cyanobacterial β-N-methylamino-l-alanine (BMAA) has been suggested as a causative or contributory factor in the development of several neurodegenerative diseases. However, no BMAA animal model has adequately shown clinical or behavioral symptoms that correspond to those seen in either Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS) or Parkinson’s Disease (PD). We present here the first data that show that when neonatal rats were exposed to BMAA on postnatal days 3, 4 and 5, but not on gestational day 14 or postnatally on days 7 or 10, several AD and/or PD-related behavioral, locomotor and cognitive deficits developed. Male rats exhibited severe unilateral hindlimb splay while whole body tremors could be observed in exposed female rats. BMAA-exposed rats failed to identify and discriminate a learned odor, an early non-motor symptom of PD, and exhibited decreased locomotor activity, decreased exploration and increased anxiety in the open field test. Alterations were also observed in the rats’ natural passive defense mechanism, and potential memory deficits and changes to the rat’s natural height avoidance behavior could be observed as early as PND 30. Spatial learning, short-term working, reference and long-term memory were also impaired in 90-day-old rats that had been exposed to a single dose of BMAA on PND 3–7. These data suggest that BMAA is a developmental neurotoxin, with specific target areas in the brain and spinal cord.

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

“…Our neuropathological data published here thus support and add to the data from the behavioural and cognitive studies published by Scott and Downing [ 55 ] that showed that rats are particularly susceptible to BMAA toxicity when exposed on PND3, presumably by altering dopamine and/or serotonin signaling in the developing brain and, subsequently also the adult central nervous system. Herlenius and Lagercrantz [ 99 ] demonstrated that the disruption of the normal timing or intensity of neurotransmitter signaling during the critical phases of brain development can lead to permanent changes in proliferation, differentiation and growth of their target cells and suggested this to provide the underlying mechanism for neurological abnormalities in adulthood.…”

“…Interestingly, Chai et al [ 106 ] reported increased cerebral microbleeds in the striatum of patients with chronic renal failure to be a significant risk factor of neurocognitive impairment. This suggests that the observed microbleeds in BMAA-exposed rats could contribute to the cognitive impairments in rats exposed to BMAA on PND3, 4 and 5 that was observed by Scott and Downing [ 55 ].…”

“…Scott and Downing [ 55 ] showed that rats exposed to 400 mg/kg BMAA on PND3, 4 and 5 exhibited several AD and/or PD-related behavioural and cognitive deficits as well as gait and postural abnormalities. In the current study we conducted a histopathological evaluation of brain and spinal cord tissue of rats with behavioural and cognitive deficits as per Scott and Downing [ 55 ]. These rats received a single dose, via subcutaneously injection, of 400 mg/kg BMAA on G14, PND3, 4, 5, 6, 7 and 10.…”

“…Administration of methamphetamine, a drug that elicits its effect by triggering a massive release of dopamine by displacing vesicles, by the inhibition of monoamine oxidase, and by enhancing the DAT-mediated reverse transport of DA transport across the plasma membrane [ 95 ] also typically results in neurodegeneration of TH-positive neurons in the substantia nigra and neuronal loss in the hippocampus, striatum and prefrontal cortex [ 96 , 97 ]. Scott and Downing [ 55 ] reported that rats exposed to BMAA on PND3, 4 and 5 demonstrated clinical symptoms and behavioural abnormalities that correspond to those observed in rats exposed to MDMA and methamphetamine, and subsequently proposed that BMAA might interfere with dopamine signaling. Interestingly, BMAA has been shown to cause alterations in serotonin and/or dopamine levels in the CNS of rats exposed neonatally [ 20 ] and in adulthood [ 98 ].…”

Role of plants, environmental toxins and physical neurotoxicological factors in Amyotrophic lateral sclerosis, Alzheimer Disease and other Neurodegenerative Diseases

“…At PND 0-2, the irst distinct patches of dopamine ibers are distributed throughout the striatum after which dopaminergic innervation increases substantially throughout the developing brain Dopamine and serotonin modulate several aspects of neuronal development, including cell proliferation, migration and differentiation, and furthermore contribute to the development of pathways needed for movement, cognition and reward. Altered dopaminergic and serotonergic signaling during development can therefore produce long lasting changes that contribute to neuro-psychiatric and neuro-degenerative disorders'' [16]. Uversky Animal models are important tools in experimental medical science for studying the pathogenesis and therapeutic intervention strategies of human diseases.…”