Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia.
Ischemic stroke is the most common life-threatening neurological disease and has limited therapeutic options. One component of ischemic neuronal death is inflammation. Here we show that doxycycline and minocycline, which are broad-spectrum antibiotics and have antiinflammatory effects independent of their antimicrobial activity, protect hippocampal neurons against global ischemia in gerbils. Minocycline increased the survival of CA1 pyramidal neurons from 10.5% to 77% when the treatment was started 12 h before ischemia and to 71% when the treatment was started 30 min after ischemia. The survival with corresponding pre- and posttreatment with doxycycline was 57% and 47%, respectively. Minocycline prevented completely the ischemia-induced activation of microglia and the appearance of NADPH-diaphorase reactive cells, but did not affect induction of glial acidic fibrillary protein, a marker of astrogliosis. Minocycline treatment for 4 days resulted in a 70% reduction in mRNA induction of interleukin-1beta-converting enzyme, a caspase that is induced in microglia after ischemia. Likewise, expression of inducible nitric oxide synthase mRNA was attenuated by 30% in minocycline-treated animals. Our results suggest that lipid-soluble tetracyclines, doxycycline and minocycline, inhibit inflammation and are neuroprotective against ischemic stroke, even when administered after the insult. Tetracycline derivatives may have a potential use also as antiischemic compounds in humans.
Yrjänheikki
J
J
A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
Keinänen
R
R
Pellikka
M
M
Hökfelt
T
T
Koistinaho
J
J
D000818:Animals; D004318:Doxycycline / Q000494:pharmacology; D005849:Gerbillinae; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D008911:Minocycline / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013754:Tetracyclines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D013754:Tetracyclines; D008911:Minocycline; D004318:Doxycycline