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Impaired volume regulation is the mechanism of excitotoxic sensitization to complement.

Publication ,  Journal Article
Loo, LS; McNamara, JO
Published in: J Neurosci
October 4, 2006

Previous work demonstrated that a brief, sublethal excitotoxic insult strikingly increased the sensitivity of cortical neurons to the cytotoxic effects of the terminal pathway of complement, a process termed "excitotoxic sensitization." Here, we sought to elucidate the cellular mechanism of excitotoxic sensitization in embryonic rat cortical neurons in vitro. Excitotoxic sensitization did not increase membrane attack complex deposition on cortical neurons and produced only a small reduction of membrane attack complex removal, because of a selective decrease of endocytic elimination. Membrane attack complexes and other osmotic stressors, namely hypotonic stress and glutamate, induced transient swelling of cortical neurons, followed by return to normal volume despite persistence of the stressor, a homeostatic response termed regulatory volume decrease (RVD). A minimal excitotoxic insult impaired this homeostatic response and sensitized neurons to cytotoxic effects of diverse osmotic stressors. Structurally distinct membrane-impermeable osmolytes, dextran and polyethylene glycol, prevented excitotoxic sensitization to diverse osmotic stressors including membrane attack complexes. Paraquat, a reactive oxygen species generator, alone was sufficient to impair RVD, and MnTBAP [Mn(III)tetrakis(4-benzoic acid)porphyrin chloride], a reactive oxygen species scavenger, prevented excitotoxin-mediated impairment of RVD. Together, these findings demonstrate that impairment of RVD is the mechanism of excitotoxic sensitization, that reactive oxygen species alone are sufficient to impair RVD, and that reactive oxygen species are necessary for excitotoxic sensitization-mediated impairment of RVD.

Duke Scholars

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

October 4, 2006

Volume

26

Issue

40

Start / End Page

10177 / 10187

Location

United States

Related Subject Headings

  • Reactive Oxygen Species
  • Rats
  • Neurons
  • Neurology & Neurosurgery
  • Glutamic Acid
  • Excitatory Amino Acid Agonists
  • Dose-Response Relationship, Drug
  • Complement System Proteins
  • Complement Membrane Attack Complex
  • Cells, Cultured
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Loo, L. S., & McNamara, J. O. (2006). Impaired volume regulation is the mechanism of excitotoxic sensitization to complement. J Neurosci, 26(40), 10177–10187. https://doi.org/10.1523/JNEUROSCI.2628-06.2006
Loo, Li Shen, and James O. McNamara. “Impaired volume regulation is the mechanism of excitotoxic sensitization to complement.J Neurosci 26, no. 40 (October 4, 2006): 10177–87. https://doi.org/10.1523/JNEUROSCI.2628-06.2006.
Loo LS, McNamara JO. Impaired volume regulation is the mechanism of excitotoxic sensitization to complement. J Neurosci. 2006 Oct 4;26(40):10177–87.
Loo, Li Shen, and James O. McNamara. “Impaired volume regulation is the mechanism of excitotoxic sensitization to complement.J Neurosci, vol. 26, no. 40, Oct. 2006, pp. 10177–87. Pubmed, doi:10.1523/JNEUROSCI.2628-06.2006.
Loo LS, McNamara JO. Impaired volume regulation is the mechanism of excitotoxic sensitization to complement. J Neurosci. 2006 Oct 4;26(40):10177–10187.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

October 4, 2006

Volume

26

Issue

40

Start / End Page

10177 / 10187

Location

United States

Related Subject Headings

  • Reactive Oxygen Species
  • Rats
  • Neurons
  • Neurology & Neurosurgery
  • Glutamic Acid
  • Excitatory Amino Acid Agonists
  • Dose-Response Relationship, Drug
  • Complement System Proteins
  • Complement Membrane Attack Complex
  • Cells, Cultured