Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline

Abstract

There is only 1 US Food and Drug Administration-approved drug for acute ischemic stroke: tissue plasminogen activator (tPA). Due to a short time window and fear of intracerebral hemorrhage (ICH), tPA remains underutilized. There is great interest in developing combination drugs to use with tPA to improve the odds of a favorable recovery and to reduce the risk of ICH. Minocycline is a broad-spectrum antibiotic that has been found to be a neuroprotective agent in preclinical ischemic stroke models. Minocycline inhibits matrix metalloproteinase-9, a biomarker for ICH associated with tPA use. Minocycline is also an anti-inflammatory agent and inhibits poly (ADP-ribose) polymerase-1. Minocycline has been safe and well tolerated in the clinical trials conducted to date.

Figure 1

The penumbra is the area of salvageable tissue that is critically time dependent. Without treatment, the penumbra is likely to convert into core or dead tissue (left). With minocycline or other neuroprotective agents, the penumbra can be “frozen” and neurons and tissue salvaged, allowing more time for tissue plasminogen activator or an interventional strategy to restore perfusion (right).