Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Department of Environmental Toxicology, Uppsala University, Uppsala, Sweden.
J Pineal Res. 2018 Aug;65(1):e12488. doi: 10.1111/jpi.12488. Epub 2018 Apr 6.
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 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.
β-N-甲基氨基-L-丙氨酸（BMAA）是一种环境神经毒素，作为谷氨酸受体激动剂，可诱导氧化应激，被认为是神经退行性疾病的一个可能风险因素。贻贝、甲壳类动物和鱼类中 BMAA 的检测表明，人类接触这种毒素的来源比预期的更为丰富。本研究旨在确定 BMAA 在松果体中的摄取及其对原代松果体细胞培养物和大鼠模型中褪黑素产生的后续影响。对 10 日龄雄性大鼠进行放射性自显影，结果显示，在给予 C-L-BMAA（0.68mg/kg）后 30 分钟至 24 小时，松果体对 BMAA 具有高选择性摄取。在 0.05-3mmol/L 的 BMAA 浓度下暴露于原代松果体细胞培养物中，褪黑素的合成减少了 57%-93%。代谢型谷氨酸受体 3（mGluR3）拮抗剂 Ly341495 和蛋白激酶 C（PKC）激活剂佛波醇-12-肉豆蔻酸-13-乙酸酯均可阻止褪黑素分泌的减少，表明 BMAA 通过 mGluR3 激活和 PKC 抑制抑制褪黑素的合成。血清分析显示，在给予 BMAA（460mg/kg）两周后评估的新生大鼠中，褪黑素浓度降低了 45%，证实了体内褪黑素合成的抑制。鉴于褪黑素是大脑中最重要的神经保护分子，BMAA 诱导的神经退行性变的病因可能包括直接兴奋毒性和氧化应激以外的机制。
