Polyamidoamine dendrimer impairs mitochondrial oxidation in brain tissue

Journal of Nanobiotechnology

Research

Júlia Visy¹  Gabriella Nyitrai²  László Héja²  István Jablonkai²  Julianna Kardos²  Ildikó Pál² 

[1] Department of Biochemical Pharmacology, Laboratory of Chemical Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Science, Budapest, Hungary;Department of Functional Pharmacology, Research Centre for Natural Sciences, Institute of Molecular Pharmacology, Hungarian Academy of Science, Budapest, Hungary;

关键词: Nanotoxicity;    PAMAM dendrimer;    Brain tissue;    Calcium enhancement;    Mitochondrial depolarization;   

DOI  :  10.1186/1477-3155-11-9

 received in 2012-12-07, accepted in 2013-03-08,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe potential nanocarrier polyamidoamine (PAMAM) generation 5 (G5-NH2) dendrimer has been shown to evoke lasting neuronal depolarization and cell death in a concentration-dependent manner. In this study we explored the early progression of G5-NH2 action in brain tissue on neuronal and astroglial cells.ResultsIn order to describe early mechanisms of G5-NH2 dendrimer action in brain tissue we assessed G5-NH2 trafficking, free intracellular Ca2+ and mitochondrial membrane potential (ΨMITO) changes in the rat hippocampal slice by microfluorimetry. With the help of fluorescent dye conjugated G5-NH2, we observed predominant appearance of the dendrimer in the plasma membrane of pyramidal neurons and glial cells within 30 min. Under this condition, G5-NH2 evoked robust intracellular Ca2+ enhancements and ΨMITO depolarization both in pyramidal neurons and astroglial cells. Intracellular Ca2+ enhancements clearly preceded ΨMITO depolarization in astroglial cells. Comparing activation dynamics, neurons and glia showed prevalence of lasting and transient ΨMITO depolarization, respectively. Transient as opposed to lasting ΨMITO changes to short-term G5-NH2 application suggested better survival of astroglia, as observed in the CA3 stratum radiatum area. We also showed that direct effect of G5-NH2 on astroglial ΨMITO was significantly enhanced by neuron-astroglia interaction, subsequent to G5-NH2 evoked neuronal activation.ConclusionThese findings indicate that the interaction of the PAMAM dendrimer with the plasma membrane leads to robust activation of neurons and astroglial cells, leading to mitochondrial depolarization. Distinguishable dynamics of mitochondrial depolarization in neurons and astroglia suggest that the enhanced mitochondrial depolarization followed by impaired oxidative metabolism of neurons may be the primary basis of neurotoxicity.

【 授权许可】

CC BY   
© Nyitrai et al.; licensee BioMed Central Ltd. 2013