The environmental neurotoxin β-N-methylamino-L-alanine inhibits melatonin synthesis in primary pinealocytes and a rat model

J Pineal Res. 2018 Aug;65(1):e12488. doi: 10.1111/jpi.12488. Epub 2018 Apr 6.

Abstract

The environmental neurotoxin β-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 30 minutes to 24 hours after 14 C-L-BMAA administration (0.68 mg/kg). Primary pinealocyte cultures exposed to 0.05-3 mmol/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 2 weeks after BMAA administration (460 mg/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.

Keywords: BMAA; DOHaD; amyotrophic lateral sclerosis/parkinsonism-dementia complex; developmental exposure; mGluR3; neurodegenerative disease; pineal gland; protein kinase C.

MeSH terms

  • Amino Acids / pharmacology
  • Amino Acids, Diamino / pharmacology*
  • Animals
  • Female
  • Male
  • Melatonin / metabolism*
  • Oxidative Stress / drug effects
  • Phorbol Esters / pharmacology
  • Pineal Gland / cytology
  • Pineal Gland / metabolism
  • Protein Kinase C / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism
  • Xanthenes / pharmacology

Substances

  • Amino Acids
  • Amino Acids, Diamino
  • LY 341495
  • Phorbol Esters
  • Receptors, Metabotropic Glutamate
  • Xanthenes
  • metabotropic glutamate receptor 3
  • beta-N-methylamino-L-alanine
  • 12-O-retinoylphorbol-13-acetate
  • Protein Kinase C
  • Melatonin