Polyamidoamine dendrimer impairs mitochondrial oxidation in brain tissue

G. Nyitrai, László Héja, I. Jablonkai, Ildikó Pál, J. Visy, J. Kardos

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: The 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.Results: In 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.Conclusion: 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.

Original languageEnglish
Article number9
JournalJournal of Nanobiotechnology
Volume11
Issue number1
DOIs
Publication statusPublished - Apr 4 2013

Fingerprint

Dendrimers
Depolarization
Neurons
Brain
Tissue
Pyramidal Cells
Oxidation
Astrocytes
Neuroglia
Chemical activation
Cell membranes
Hippocampal CA3 Region
Cell Membrane
Mitochondrial Dynamics
Cytophotometry
Intracellular Membranes
Mitochondrial Membrane Potential
Fluorescent Dyes
Cell Death
Cell death

Keywords

  • Brain tissue
  • Calcium enhancement
  • Mitochondrial depolarization
  • Nanotoxicity
  • PAMAM dendrimer

ASJC Scopus subject areas

  • Molecular Medicine
  • Bioengineering
  • Biomedical Engineering
  • Applied Microbiology and Biotechnology
  • Medicine (miscellaneous)
  • Pharmaceutical Science

Cite this

Polyamidoamine dendrimer impairs mitochondrial oxidation in brain tissue. / Nyitrai, G.; Héja, László; Jablonkai, I.; Pál, Ildikó; Visy, J.; Kardos, J.

In: Journal of Nanobiotechnology, Vol. 11, No. 1, 9, 04.04.2013.

Research output: Contribution to journalArticle

@article{b3ed4cbdcfef4adc819baad554019844,
title = "Polyamidoamine dendrimer impairs mitochondrial oxidation in brain tissue",
abstract = "Background: The 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.Results: In 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.Conclusion: 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.",
keywords = "Brain tissue, Calcium enhancement, Mitochondrial depolarization, Nanotoxicity, PAMAM dendrimer",
author = "G. Nyitrai and L{\'a}szl{\'o} H{\'e}ja and I. Jablonkai and Ildik{\'o} P{\'a}l and J. Visy and J. Kardos",
year = "2013",
month = "4",
day = "4",
doi = "10.1186/1477-3155-11-9",
language = "English",
volume = "11",
journal = "Journal of Nanobiotechnology",
issn = "1477-3155",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Polyamidoamine dendrimer impairs mitochondrial oxidation in brain tissue

AU - Nyitrai, G.

AU - Héja, László

AU - Jablonkai, I.

AU - Pál, Ildikó

AU - Visy, J.

AU - Kardos, J.

PY - 2013/4/4

Y1 - 2013/4/4

N2 - Background: The 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.Results: In 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.Conclusion: 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.

AB - Background: The 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.Results: In 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.Conclusion: 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.

KW - Brain tissue

KW - Calcium enhancement

KW - Mitochondrial depolarization

KW - Nanotoxicity

KW - PAMAM dendrimer

UR - http://www.scopus.com/inward/record.url?scp=84875688528&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875688528&partnerID=8YFLogxK

U2 - 10.1186/1477-3155-11-9

DO - 10.1186/1477-3155-11-9

M3 - Article

C2 - 23556550

AN - SCOPUS:84875688528

VL - 11

JO - Journal of Nanobiotechnology

JF - Journal of Nanobiotechnology

SN - 1477-3155

IS - 1

M1 - 9

ER -