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Acta Neuropathol. 2015 Dec;130(6):799-814. doi: 10.1007/s00401-015-1497-x. Epub 2015 Oct 31.

Tracking CNS and systemic sources of oxidative stress during the course of chronic neuroinflammation.

Author information

1
German Rheumatism Research Center, Berlin, Germany.
2
Department of Neurology, NeuroCure Clinical Research Center, Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.
3
Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
4
Intravital Imaging and Immune Dynamics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
5
Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
6
Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany.
7
DZNE-German Center for Neurodegenerative Diseases, Berlin, Germany.
8
Department of Paediatrics I, Neonatology, University Hospital Essen, Essen, 45122, Germany.
9
Department of Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité-Universitätsmedizin Berlin, Cluster of Excellence NeuroCure and BIH, Berlin, Germany.
10
German Rheumatism Research Center, Berlin, Germany. niesner@drfz.de.
11
Institut für Neuropathologie, Charité-Universitätsmedizin Berlin, Berlin, Germany. helena.radbruch@charite.de.

Abstract

The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation.

KEYWORDS:

Fluorescence lifetime microscopy; Intravital imaging; Multiple sclerosis; Neuronal dysfunction; Oxidative stress; Oxidative stress memory

PMID:
26521072
PMCID:
PMC4654749
DOI:
10.1007/s00401-015-1497-x
[Indexed for MEDLINE]
Free PMC Article

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