A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window

The only treatment of patients with acute ischemic stroke is thrombolytic t herapy, which benefits only a fraction of stroke patients. Both human and e xperimental studies indicate that ischemic stroke involves secondary inflam mation that significantly contributes to the outcome after ischemic insult. Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobia l action. Because tetracycline treatment is clinically well tolerated, we i nvestigated whether minocycline protects against focal brain ischemia with a wide therapeutic window. Using a rat model of transient middle cerebral a rtery occlusion, we show that daily treatment with minocycline reduces cort ical infarction volume by 76 +/- 22% when the treatment is started 12 h bef ore ischemia and by 63 +/- 35% when started even 4 h after the onset of isc hemia, The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-lp-converting enz yme, and reduces cyclooxygenase-2 expression and prostaglandin E-2 producti on. Minocycline had no effect on astrogliosis or spreading depression, a wa ve of ionic transients thought to contribute to enlargement of cortical inf arction. Treatment with minocycline may act directly on brain cells, becaus e cultured primary neurons were also salvaged from glutamate toxicity. Mino cycline may represent a prototype of an antiinflammatory compound that prov ides protection against ischemic stroke and has a clinically relevant thera peutic window.