Brain anti-cytoxic edema agents.

The work described in this chapter has indicated that improved outcome from an experimental head injury model can be achieved by drugs which are non-diuretic derivatives of loop diuretics, namely indanyl and fluorenyl compounds which are derivatives of ethacrynic acid. These drugs were originally identified by us on the basis of their efficacy in inhibiting [K+]-stimulated, HCO3(-)-dependent swelling of brain cerebrocortical slices. Swelling of glial cells (astrocytes) has long been known to be associated with such slice swelling and astrocyte swelling is a major locus of cytotoxic or cellular brain edema. Qualitative and quantitative electron microscope studies have shown that L644,711, a particularly effective member of the fluorenyl class of drugs, inhibits astrocytic swelling associated with an experimental animal head injury model. We have suggested that astrocytic swelling in pathological states may be partly due to activation of Cl-/HCO3- and Na+/H+ exchange systems driven by increased astrocytic intracellular hydration of CO2, and recent work has indeed shown that the ability of the indanyl and fluorenyl drugs to inhibit brain slice swelling and protect against head injury correlates closely with their ability to inhibit Cl-/HCO3- exchange. All these data suggest that astrocytic swelling, which seems to precede neuronal degeneration and breakdown of the blood-brain barrier, is deleterious and that prevention of such swelling can lead to effective therapy. We have used primary astrocytic cultures to explore reasons why astrocytic swelling could be harmful. Exposing such astrocytes to hypotonic medium causes rapid swelling with a slower return to normal volume in the continued presence of hypotonic medium, a process known as regulatory volume decrease or RVD. Such RVD is associated with marked release of several amino acids, including L-glutamate. L644,711 and other Cl-/HCO3- transport inhibitors such as SITS and furosemide, but not the selective Na+ + K+ + 2Cl- co-transport inhibitor bumetanide, inhibit such swelling-induced release of L-glutamate. Thus, L644,711 and other drugs may be effective in promoting recovery from head injury and other pathological states in which astrocytic swelling occurs either by initially preventing the swelling or inhibiting the release of excitotoxic excitatory amino acids if swelling does occur, perhaps depending at what time the drug is given.