PMID- 21900578
OWN - NLM
STAT- MEDLINE
DCOM- 20111031
LR  - 20220309
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 31
IP  - 36
DP  - 2011 Sep 7
TI  - Microglial cells contribute to endogenous brain defenses after acute neonatal 
      focal stroke.
PG  - 12992-3001
LID - 10.1523/JNEUROSCI.2102-11.2011 [doi]
AB  - Macrophages are viewed as amplifiers of ischemic brain injury, but the origin of 
      injury-producing macrophages is poorly defined. The role of resident brain 
      macrophages-microglial cells-in stroke remains controversial. To determine 
      whether microglial cells exert injurious effects after neonatal focal stroke, we 
      selectively depleted these cells with intracerebral injection of 
      liposome-encapsulated clodronate before transient middle cerebral artery 
      occlusion in postnatal day 7 rats. Phagocytosis of apoptotic neurons by activated 
      microglia was poor in animals with unmanipulated microglia, and depletion of 
      these cells did not increase the number of apoptotic neurons. Lack of microglia 
      increased the brain levels of several cytokines and chemokines already elevated 
      by ischemia-reperfusion, and also increased the severity and volume of injury, 
      suggesting that microglial cells contribute to endogenous protection during the 
      subacute injury phase. Then, to determine whether accumulation of reactive oxygen 
      species in microglia adversely affects phagocytosis of dying neurons and 
      contributes to injury, we delivered reduced glutathione (GSH) into microglia, 
      again using liposomes. Remarkably, pharmacologically increased intracellular GSH 
      concentrations in microglia induced superoxide accumulation in lipid rafts in 
      these cells, further increased the brain levels of macrophage chemoattractants, 
      and exacerbated injury. Together, these data show that microglia are part of the 
      endogenous defense mechanisms and that, while antioxidants can protect the 
      injured neonatal brain, high levels of reducing equivalents in activated 
      microglia, GSH, trigger superoxide production, favor the reorganization of 
      lipids, amplify local inflammation and exacerbate injury.
FAU - Faustino, Joel V
AU  - Faustino JV
AD  - Department of Neurology, University of California, San Francisco, San Francisco, 
      California 94143-0663, USA.
FAU - Wang, Xia
AU  - Wang X
FAU - Johnson, Cali E
AU  - Johnson CE
FAU - Klibanov, Alexander
AU  - Klibanov A
FAU - Derugin, Nikita
AU  - Derugin N
FAU - Wendland, Michael F
AU  - Wendland MF
FAU - Vexler, Zinaida S
AU  - Vexler ZS
LA  - eng
GR  - R01NS44025/NS/NINDS NIH HHS/United States
GR  - R01NS055915/NS/NINDS NIH HHS/United States
GR  - R01 NS055915/NS/NINDS NIH HHS/United States
GR  - R01 NS044025/NS/NINDS NIH HHS/United States
GR  - P50 NS035902/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 3.4.22.- (Caspase 3)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Animals, Newborn/*physiology
MH  - Blotting, Western
MH  - Brain/*physiology
MH  - Caspase 3/physiology
MH  - Cell Death/physiology
MH  - Chemokines/analysis/biosynthesis
MH  - Cytokines/analysis/biosynthesis
MH  - Echo-Planar Imaging
MH  - Female
MH  - Fluorescent Antibody Technique
MH  - Glutathione/metabolism/pharmacology
MH  - Inflammation/pathology
MH  - Lipid Metabolism/physiology
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Microglia/*physiology
MH  - Phagocytosis/physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reactive Oxygen Species/metabolism
MH  - Reperfusion Injury/pathology
MH  - Stroke/*physiopathology
PMC - PMC3539822
MID - NIHMS323173
EDAT- 2011/09/09 06:00
MHDA- 2011/11/01 06:00
PMCR- 2012/03/07
CRDT- 2011/09/09 06:00
PHST- 2011/09/09 06:00 [entrez]
PHST- 2011/09/09 06:00 [pubmed]
PHST- 2011/11/01 06:00 [medline]
PHST- 2012/03/07 00:00 [pmc-release]
AID - 31/36/12992 [pii]
AID - 3719974 [pii]
AID - 10.1523/JNEUROSCI.2102-11.2011 [doi]
PST - ppublish
SO  - J Neurosci. 2011 Sep 7;31(36):12992-3001. doi: 10.1523/JNEUROSCI.2102-11.2011.