Microglia provide neuroprotection after ischemia.
Many neurological insults are accompanied by a marked acute inflammatory reaction, involving the activation of microglia. Using a model of exogenous application of fluorescence-labeled BV2 microglia in pathophysiologically relevant concentrations onto organotypic hippocampal slice cultures, we investigated the specific effects of microglia on neuronal damage after ischemic injury. Neuronal cell death after oxygen-glucose deprivation (OGD) was determined by propidium iodide incorporation and Nissl staining. Migration and interaction with neurons were analyzed by time resolved 3-D two-photon microscopy. We show that microglia protect against OGD-induced neuronal damage and engage in close physical cell-cell contact with neurons in the damaged brain area. Neuroprotection and migration of microglia were not seen with integrin regulator CD11a-deficient microglia or HL-60 granulocytes. The induction of migration and neuron-microglia interaction deep inside the slice was markedly increased under OGD conditions. Lipopolysaccharide-prestimulated microglia failed to provide neuroprotection after OGD. Pharmacological interference with microglia function resulted in a reduced neuroprotection. Microglia proved to be neuroprotective even when applied up to 4 h after OGD, thus defining a "protective time window." In acute injury such as trauma or stroke, appropriately activated microglia may primarily have a neuroprotective role. Anti-inflammatory treatment within the protective time window of microglia would therefore be counterintuitive.
Neumann
Jens
J
Leibniz Institute for Neurobiology, Project Group Neuropharmacology, Magdeburg, Germany.
Gunzer
Matthias
M
Gutzeit
Herwig O
HO
Ullrich
Oliver
O
Reymann
Klaus G
KG
Dinkel
Klaus
K
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002545:Brain Ischemia / Q000473:pathology*; D040881:CD11a Antigen; D016923:Cell Death; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D006098:Granulocytes / Q000378:metabolism; D018922:HL-60 Cells; D006624:Hippocampus; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D040881:CD11a Antigen; D000841:Anisomycin; D008911:Minocycline; D005947:Glucose