One consequence of traumatic (head injury) and ischemic (stroke) brain injury that has been largely ignored in therapeutics development is glial swelling. Glial (astrocytic) swelling causes impingement on blood capillaries, reducing the flow of oxygen and nutrients to brain cells, and causes astrocytes to release, rather than take up, neurotransmitters, further potentiating neurologic damage. The swelling phenomenon is mediated by a Cl- -dependent mechanism, involving influx of Cl- ions into the glia. L-644,711, a fluorenone derivative of ethacrynic acid, is a potent inhibitor of astrocytic Cl- channels and has been shown to be neuroprotective in models of traumatic injury both in vitro and in vivo. We propose to examine whether L-644,711, an amidine derivative of it and four novel derivatives are able to reduce astrocytic swelling and neurotransmitter release in vitro, and whether L-644,711 and the derivative deemed most promising as indicated by the in vitro data are neuroprotective in in vivo models of focal and global ischemia.
