Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection.
Previous studies in a mouse model of neonatal excitotoxic brain damage mimicking the brain lesions in human cerebral palsy showed microglial activation within 24 h after intracerebral injection of the glutamatergic analog ibotenate. Using this model, we studied the expression of CD-45 antigen, a marker of blood-derived cells, by these activated microglial cells labeled by Griffonia simplicifolia I isolectin B4. Immunohistochemistry performed during early development of excitotoxic lesions showed that most cells labeled with the isolectin B4 were CD-45-negative, suggesting that these early activated microglial cells were deriving chiefly from resident microglia and not from circulating monocytes. We also directly tested the hypothesis that activated resident microglia and/or blood-derived monocytes play a role in the pathophysiology of excitotoxic brain damage. Repeated i.p. administrations of chloroquine, chloroquine+colchicine, minocycline, or an anti-MAC1 antibody coupled to the toxin saporin before and/or after ibotenate injection induced a significant reduction in the density of isolectin B4-positive cells. This inhibition of resident microglial and/or blood-derived monocytes activation was accompanied by a significant reduction in the severity of ibotenate-induced brain lesions (up to 79% lesion size reduction with the highest minocycline dose) as well as of ibotenate-induced cortical caspase-3 activation (49% reduction).
INSERM E 9935, Service de Neurologie Pédiatrique, Hôpital Robert-Debré, 48 BD Sérurier, 75019 Paris, France.
M-A
MA
Dommergues
F
F
Plaisant
C
C
Verney
P
P
Gressens
D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018501:Antirheumatic Agents; D001921:Brain; D001930:Brain Injuries / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D016923:Cell Death; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology*; D002547:Cerebral Palsy / Q000378:metabolism / Q000473:pathology; D002738:Chloroquine / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006023:Glycoproteins; D007051:Ibotenic Acid; D007150:Immunohistochemistry; D037102:Lectins / Q000378:metabolism; D017254:Leukemic Infiltration / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D008911:Minocycline / Q000494:pharmacology; D009474:Neurons; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013194:Staining and Labeling; D013997:Time Factors
D000900:Anti-Bacterial Agents; D018501:Antirheumatic Agents; D006023:Glycoproteins; D037102:Lectins; D016177:Macrophage-1 Antigen; D018696:Neuroprotective Agents; D018809:Proliferating Cell Nuclear Antigen; C473590:isolectin B4-binding glycoprotein, mouse; D007051:Ibotenic Acid; D002738:Chloroquine; D017493:Leukocyte Common Antigens; D008911:Minocycline