Insights into Mechanisms of Blood-Brain Barrier Permeability – Roles of Free Radicals, Matrix Metalloproteinsases, and Caveolin-1

Free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), are important mediators in cerebral ischemia-reperfusion injury and other neurological diseases. Accumulation of toxic free radicals not only increase the susceptibility of brain tissue to ischemic damage but also trigger numerous molecular cascades, leading to increased blood-brain barrier (BBB) permeability, brain edema, hemorrhage and inflammation, and brain death. Matrix metalloproteinases (MMPs) are one of the major targets in BBB breakdown. MMPs are proteolytic zinc-containing enzymes responsible for degradation of the extracellular matrix around cerebral blood vessels and neurons. Free radicals can activate MMPs and induce the degradations of tight junctions (TJs), leading to BBB breakdown. Recent studies indicate that caveolin-1, a 22 kDa membrane integral protein located at caveolae, can inhibit RNS production and MMPs activity, protect TJ proteins from degradation, and reduce the BBB permeability in cerebral ischemia-reperfusion injury. The interaction of RNS, caveolin-1, and MMPs forms a positive feedback loop which provides amplified impacts on BBB dysfunction during cerebral ischemia-reperfusion injury. Herein, we review the recent progress in the interaction of RNS, caveolin-1, and MMPs and the impact of the interaction on BBB permeability. For drug discovery, we summarize current evidence about antioxidant therapy in regulations of MMPs and caveolin-1 and anticipate the potential of developing antioxidants for the treatment of stroke and other neurological diseases. In conclusion, the interaction of RNS, caveolin-1, and MMPs could be a critical signal pathway in BBB disruption and infarction enlargement during cerebral ischemia-reperfusion injury and other neurological diseases