Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia

Abstract

Ischemic stroke is the most common lifethreatening neurological disease and has limited therapeutic options. One component of ischemic neuronal death is inf lammation. Here we show that doxycycline and minocycline, which are broad-spectrum antibiotics and have antiinf lammatory 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 ischemiainduced 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-1␤-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 inf lammation 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.

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

“…For instance, minocycline is neuroprotective and reduces damage to the blood-brain barrier in models of ischemic stroke by attenuating microglial activation. 18 This effect could be mediated by inhibition of TNF-a production, since a similar protective effect was observed in TNF-a knockout or in wildtype mice that were treated with minocycline prior to the intraparenchymal injection of a dopamine neurotoxin. 28 Minocycline may also have therapeutic benefit for the treatment of HIV-induced neuroinflammation, as minocycline reduced the severity of encephalitis, suppressed viral load in the brain and decreased the expression of brain inflammatory markers in a Simian immunodeficiency model of HIV.…”

“…Minocycline has potent anti-inflammatory effects independent from its microbicidal properties, as it is well-known to inhibit macrophage and microglial activation. Of all the tetracyclines, it has the greatest permeability through the blood-brain barrier, 17 and it confers therapeutic benefits in many CNS disease models, including ischemia, 18 Parkinson disease, 19 amyotrophic lateral sclerosis 20 and multiple sclerosis. 17 The tryptophan analog 1-methyltryptophan (1-MT) was chosen for the second approach.…”

Inflammation after Intracerebral Hemorrhage

“…Evidence suggests that tetracycline derivatives provide neuroprotection against global brain ischemia (Yrjanheikki et al, 1998), amyotrophic lateral sclerosis (Van Den Bosch et al, 2002), and Parkinson disease (Wu et al, 2002a), and that this neuroprotection involves the inhibition of microglial activation. Recently, a study by Power et al (2003) demonstrated that, in a rat model of ICH, 7-day treatment with minocycline initiated 1 h after collagenase injection protected the morphology of neurons and improved functional recovery.…”

Microglial Activation in Stroke: Therapeutic Targets

“…Minocycline was shown to suppress microglial activation and improve neuronal survival after brain ischemia. 228,229 Minocycline and other PARP-1 inhibitors are entering clinical trials for treatment of stroke and other conditions. 230 -232 …”