Tetracyclines Inhibit Microglial Activation and are Neuroprotective in Global Brain Ischemia

• Published in: Proceedings of the National Academy of Sciences - PNAS 1998-12, Vol.95 (26), p.15769-15774
• Main Authors: Yrjanheikki, Juha, Keinanen, Riitta, Pellikka, Milla, Hokfelt, Tomas, Koistinaho, Jari
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Brain; Brain ischemia; Dosage; Doxycycline - pharmacology; Gerbillinae; Glial Fibrillary Acidic Protein - analysis; Glial Fibrillary Acidic Protein - genetics; Hippocampus - drug effects; Hippocampus - pathology; Humans; Ice; Ischemia; Ischemic Attack, Transient - pathology; Ischemic Attack, Transient - prevention & control; Male; Medicin och hälsovetenskap; Messenger RNA; Microglia; Microglia - drug effects; Microglia - pathology; Microglia - physiology; Minocycline - pharmacology; Neurology; Neurons; Neuroprotective Agents - pharmacology; Pyramidal cells; Pyramidal Cells - drug effects; Pyramidal Cells - pathology; Pyramidal Cells - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Stroke; Strokes; Tetracyclines - pharmacology; Transcription, Genetic - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.26.15769

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.