Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia

Proceedings of the National Academy of Sciences of the United States of America - Tập 95 Số 26 - Trang 15769-15774 - 1998
Juha Yrjänheikki1, Riitta Keinänen1, M. Pellikka1, Tomas Hökfelt1, Jari Koıstınaho1
1A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Neurology, Kuopio University Hospital, P.O. Box 1777, 70211 Kuopio, Finland; and Department of Neuroscience, Karolinska Institute, S-171-77, Stockholm, Sweden

Tóm tắt

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-1β-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.

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Thông tin xuất bản

Proceedings of the National Academy of Sciences of the United States of America

Tập 95 Số 26

15769-15774

Thông tin tác giả