Abstract: Methods are provided for inhibiting cell adhesion molecule cleavage in brain tissue of a host. In the subject methods, an effective amount of a protease inhibitor, particularly serine protease inhibitors, such as those that inhibit tPA and related proteases, is administered to the host. The subject methods find use in the treatment and prevention of pathophysiology and neuropathology in a host, such as the treatment of a variety of pathological conditions resulting from pathophysiology and/or excitotoxicity. Specific pathological conditions in which the subject methods find use include epilepsy (and related seizure states) and neuronal damage associated with excessive glutamate activity, e.g. resulting from an acute event such as hypoxia, head trauma or stroke.