title: Polyamidoamine dendrimer impairs mitochondrial oxidation in brain tissue.
abstract: BACKGROUND
  The potential nanocarrier polyamidoamine (PAMAM) generation 5 (G5-NH(2)) 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-NH(2) action in brain tissue on neuronal and astroglial cells.
  
  
  RESULTS
  In order to describe early mechanisms of G5-NH(2) dendrimer action in brain tissue we assessed G5-NH(2) trafficking, free intracellular Ca(2+) and mitochondrial membrane potential (Ψ(MITO)) changes in the rat hippocampal slice by microfluorimetry. With the help of fluorescent dye conjugated G5-NH(2), we observed predominant appearance of the dendrimer in the plasma membrane of pyramidal neurons and glial cells within 30 min. Under this condition, G5-NH(2) evoked robust intracellular Ca(2+) enhancements and Ψ(MITO) depolarization both in pyramidal neurons and astroglial cells. Intracellular Ca(2+) enhancements clearly preceded Ψ(MITO) depolarization in astroglial cells. Comparing activation dynamics, neurons and glia showed prevalence of lasting and transient Ψ(MITO) depolarization, respectively. Transient as opposed to lasting Ψ(MITO) changes to short-term G5-NH(2) application suggested better survival of astroglia, as observed in the CA3 stratum radiatum area. We also showed that direct effect of G5-NH(2) on astroglial Ψ(MITO) was significantly enhanced by neuron-astroglia interaction, subsequent to G5-NH(2) evoked neuronal activation.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of Functional Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Science, Budapest, Hungary. nyitrai.gabriella@ttk.mta.hu
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nyitrai
authors.forename: László
authors.initials: L
authors.lastname: Héja
authors.forename: István
authors.initials: I
authors.lastname: Jablonkai
authors.forename: Ildikó
authors.initials: I
authors.lastname: Pál
authors.forename: Júlia
authors.initials: J
authors.lastname: Visy
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D020013:Calcium Signaling; D002462:Cell Membrane / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry / Q000633:toxicity*; D005456:Fluorescent Dyes / Q000032:analysis / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects*; D011073:Polyamines / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D050091:Dendrimers; D005456:Fluorescent Dyes; C531249:Poly(amidoamine); D011073:Polyamines
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