Clot-Busting Drugs Made Safer by Blocking Toxic Effects

Genetically removing LRP1-- a molecule that appears to transmit inflammation signals triggered by tissue plasminogen activator (tPA)--from microglia brain cells in mice softens tPA's impact on the brain, according to a new study.

Researchers at Emory University School of Medicine (Emory, Atlanta, GA, USA) found that middle cerebral artery occlusion (MCAO) induced microglial rain cell activation in both wild type and plasminogen-deficient mice. However, MCAO-induced microglial activation was significantly decreased in tPA-deficient mice and in mice that lacked LRP1 (a low-density lipoprotein receptor gene also found in neurons and astrocytes) in the same cells. The researchers then observed a significant increase in microglial activation when tPA-deficient mice received treatment with murine tPA after MCAO. Finally, treatment of mice with LRP1-deficient microglia cells with tPA did not have an effect on the extent of microglial activation. The researchers concluded that these results indicate that the interaction between tPA (a serine proteinase) and LRP1 induces microglial activation with the generation of an inflammatory response in the ischemic brain, suggesting a cytokine-like role for tPA in the central nervous system (CNS).

"tPA is a protein released naturally by the body in response to a blood clot, but it's clearly not just lysing the clot” said lead author Manuel Yepes, M.D., Ph.D., an assistant professor of neurology at Emory. "Our strategy was to show that by blocking LRP1, you could prevent the inflammatory response to tPA. This can be done either genetically, by deleting LRP1, or perhaps pharmacologically.”

Since the introduction of the life-saving clot-busting drug tPA more than a decade ago, evidence has been accumulating that tPA can be a double-edged sword for a brain affected by stroke. Doctors in community hospitals are often reluctant to administer tPA to patients who appear to be having a stroke, since tPA also increases the permeability of the blood-brain barrier, crossing into the brain tissue and generating inflammation, thus contributing to brain cell damage.

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Emory University School of Medicine