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The environmental neurotoxin beta-N-methylamino-L-alanine inhibits melatonin synthesis in primary pinealocytes and a rat model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.ORCID iD: 0000-0002-5386-2400
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2018 (English)In: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 65, no 1, article id e12488Article in journal (Refereed) Published
Abstract [en]

The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is a glutamate receptor agonist that can induce oxidative stress and has been implicated as a possible risk factor for neurodegenerative disease. Detection of BMAA in mussels, crustaceans, and fish illustrates that the sources of human exposure to this toxin are more abundant than previously anticipated. The aim of this study was to determine uptake of BMAA in the pineal gland and subsequent effects on melatonin production in primary pinealocyte cultures and a rat model. Autoradiographic imaging of 10-day-old male rats revealed a high and selective uptake in the pineal gland at 30minutes to 24hours after C-14-L-BMAA administration (0.68mg/kg). Primary pinealocyte cultures exposed to 0.05-3mmol/L BMAA showed a 57%-93% decrease in melatonin synthesis in vitro. Both the metabotropic glutamate receptor 3 (mGluR3) antagonist Ly341495 and the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate prevented the decrease in melatonin secretion, suggesting that BMAA inhibits melatonin synthesis by mGluR3 activation and PKC inhibition. Serum analysis revealed a 45% decrease in melatonin concentration in neonatal rats assessed 2weeks after BMAA administration (460mg/kg) and confirmed an inhibition of melatonin synthesis in vivo. Given that melatonin is a most important neuroprotective molecule in the brain, the etiology of BMAA-induced neurodegeneration may include mechanisms beyond direct excitotoxicity and oxidative stress.

Place, publisher, year, edition, pages
WILEY , 2018. Vol. 65, no 1, article id e12488
Keywords [en]
amyotrophic lateral sclerosis, parkinsonism-dementia complex, BMAA, developmental exposure, DOHaD, mGluR3, neurodegenerative disease, pineal gland, protein kinase C
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-360183DOI: 10.1111/jpi.12488ISI: 000437132700009PubMedID: 29528516OAI: oai:DiVA.org:uu-360183DiVA, id: diva2:1247822
Funder
Swedish Research Council FormasCarl Tryggers foundation Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2018-09-13Bibliographically approved

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Pierozan, PaulaAndersson, MarieBrandt, IngvarKarlsson, Oskar

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