Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia

TLDR

Ischemic stroke is the most common life‑threatening neurological disease with limited therapeutic options, and inflammation contributes to neuronal death. Broad‑spectrum tetracyclines doxycycline and minocycline protect gerbil hippocampal CA1 neurons from global ischemia, raising survival from 10.5 % to 77 % when given 12 h before and 71 % when given 30 min after insult, suppress microglial activation and inflammatory cytokine expression, and demonstrate neuroprotection even when administered after the insult, suggesting therapeutic potential in humans.

Abstract

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.