Polyamidoamine dendrimer impairs mitochondrial oxidation in brain tissue

Abstract

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.

Comparative toxicological assessment of PAMAM and thiophosphoryl dendrimers using embryonic zebrafish

“…19 An increasing number of studies in diverse cell lines have shown that exposure to cationic dendrimers results in cell membrane permeability, cellular lysis, and cytotoxicity. 9,[20][21][22][23] Recent studies in mice and zebrafish (Danio rerio) have also shown polyamidoamine (PAMAM) dendrimers with amine terminated groups affected blood-clot formation when administered intravenously, while neutral and anionic dendrimers of the same generation demonstrated no observable vascular complications. 24,25 The authors suggest that these effects are driven by the high affinity amine for platelets or vascular endothelium.…”

“…[4][5][6][7] The low polydispersity index and the ability to precisely control their surface chemistry make dendrimers useful for medical imaging, enhancing the solubility and/or bioavailability of drugs, brain-target drug therapy, and specific targeting mechanism for anti-cancer therapeutics and gene therapy. [8][9][10] The stability, precise size, and defined chemistry of dendrimers also make them ideal for the development of structure-property relationships.…”

Interaction of SiO2 nanoparticles with neuronal cells: Ionic mechanisms involved in the perturbation of calcium homeostasis

“…Apart from silica NPs , data on the perturbations of calcium signaling mechanisms induced by NPs are still scarce (see e.g. Huang et al, 2010;Koeneman et al, 2010) and this is particularly true for neuronal cells (Guo et al, 2013;Haase et al, 2012;Nyitrai et al, 2013;Tang et al, 2008aTang et al, , 2008b, as recently reviewed (Lovisolo et al, 2014).…”

Nanoparticles for Brain-Specific Drug and Genetic Material delivery, Imaging and Diagnosis

“…PAMAM dendrimers exhibit neuronal toxicity. For example, unmodified PAMAM G5-NH 2 induces mitochondrial membrane potential depolarization in neurons and astroglial cells [55] and activates autophagy [56]. PAMAM dendrimers also increase reactive oxygen species and DNA damage in a generation-dependent manner [57].…”