Published Online
on February 23, 2006

A more recent version of this article appeared on April 1, 2006

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Submitted on August 9, 2005
Revised on September 29, 2005
Accepted on November 8, 2005

Microglia Potentiate Damage to Blood-Brain Barrier Constituents. Improvement by Minocycline In Vivo and In Vitro

Midori A. Yenari MD^*; Lijun Xu MD; Xian Nan Tang MD; Yanli Qiao MD; and Rona G. Giffard MD, PhD

From the Departments of Anesthesia (L.X., X.N.T., Y.Q., R.G.G.) and Neurosurgery (R.G.G.), Stanford University School of Medicine, California; and Department of Neurology (M.A.Y., X.N.T.), University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center, California.

^* To whom correspondence should be addressed. E-mail: yenari{at}alum.mit.edu.

Background--Blood-brain barrier (BBB) disruption after stroke can worsen ischemic injury by increasing edema and causing hemorrhage. We determined the effect of microglia on the BBB and its primary constituents, endothelial cells (ECs) and astrocytes, after ischemia using in vivo and in vitro models.

Methods and Results--Primary astrocytes, ECs, or cocultures were prepared with or without added microglia. Primary ECs were more resistant to oxygen-glucose deprivation/reperfusion than astrocytes. ECs plus astrocytes showed intermediate vulnerability. Microglia added to cocultures nearly doubled cell death. This increase was prevented by minocycline and apocynin. In vivo, minocycline reduced infarct volume and neurological deficits and markedly reduced BBB disruption and hemorrhage in mice after experimental stroke.

Conclusions--Inhibition of microglial activation may protect the brain after ischemic stroke by improving BBB viability and integrity. Microglial inhibitors may prove to be an important treatment adjunct to fibrinolysis.

Key words: blood-brain barrier • inflammation • ischemia • microglia

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