Tulpule Ketki, Hohnholt Michaela C, Dringen Ralf
Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Centre for Environmental Research and Sustainable Technology, Leobener Strasse, Bremen, Germany.
J Neurochem. 2013 Apr;125(2):260-72. doi: 10.1111/jnc.12170. Epub 2013 Feb 24.
Formaldehyde is endogenously produced in the human body and brain levels of this compound are elevated in neurodegenerative conditions. Although the toxic potential of an excess of formaldehyde has been studied, little is known on the molecular mechanisms underlying its neurotoxicity as well as on the ability of neurons to metabolize formaldehyde. To address these topics, we have used cerebellar granule neuron cultures as model system. These cultures express mRNAs of various enzymes that are involved in formaldehyde metabolism and were remarkably resistant toward acute formaldehyde toxicity. Cerebellar granule neurons metabolized formaldehyde with a rate of around 200 nmol/(h × mg) which was accompanied by significant increases in the cellular and extracellular concentrations of formate. In addition, formaldehyde application significantly increased glucose consumption, almost doubled the rate of lactate release from viable neurons and strongly accelerated the export of the antioxidant glutathione. The latter process was completely prevented by inhibition of the known glutathione exporter multidrug resistance protein 1. These data indicate that cerebellar granule neurons are capable of metabolizing formaldehyde and that the neuronal glycolysis and glutathione export are severely affected by the presence of formaldehyde.
甲醛在人体中内源性产生，在神经退行性疾病中该化合物的脑内水平会升高。尽管已经对过量甲醛的潜在毒性进行了研究，但对于其神经毒性的分子机制以及神经元代谢甲醛的能力却知之甚少。为了解决这些问题，我们使用小脑颗粒神经元培养物作为模型系统。这些培养物表达参与甲醛代谢的各种酶的mRNA，并且对急性甲醛毒性具有显著抗性。小脑颗粒神经元以约200 nmol/（h×mg）的速率代谢甲醛，同时伴随着细胞内和细胞外甲酸浓度的显著增加。此外，施加甲醛显著增加了葡萄糖消耗，使存活神经元的乳酸释放速率几乎翻倍，并强烈加速了抗氧化剂谷胱甘肽的输出。通过抑制已知的谷胱甘肽转运蛋白多药耐药蛋白1，完全阻止了后一过程。这些数据表明，小脑颗粒神经元能够代谢甲醛，并且甲醛的存在会严重影响神经元糖酵解和谷胱甘肽输出。
