Short and long-term motor and behavioral effects of diazoxide and dimethyl sulfoxide administration in the mouse after traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a worldwide phenomenon that affects all ages and socioeconomic classes and results in varying degrees of immediate and delayed motor, cognitive, and emotional deficiencies. A plethora of pharmacologic interventions that target recognized initiators and propagators of pathology are being investigated in an attempt to ameliorate secondary injury processes that follow primary injury. Diazoxide (DZ), a KATP channel activator, has been shown to provide short- and long-term protective effects in a variety of in vitro and in vivo cerebral ischemia models. However, the effects of DZ on behavioral outcome following TBI have not been investigated. TBI was induced in male C57BL/6J mice by controlled cortical impact (CCI) and followed by intraperitoneal administration of either normal saline, dimethyl sulfoxide (DMSO), or 2.5mg/kg DZ in DMSO, 30min post-injury and daily for three days. Open field and beam walk performances were used to assess motor and behavioral function 1, 7, and 14days following injury. Spatial learning and memory were assessed three weeks following injury using the Morris water maze. Injured mice were significantly impaired on the beam-walk and Morris water maze tasks, and were hyperactive and anxious in an open field environment. On post-injury days 1 and 14, mice treated with DMSO exhibited an increase in the amount of time required to perform the beam walk task. In addition, animals exposed to DMSO or DZ+DMSO exhibited slower swimming speed in the Morris water maze on the final day of testing. There was no therapeutic effect, however, of the treatment or vehicle on open field behavior or learning and memory function in the Morris water maze. In summary, CCI produced significant long-term impairment of motor, memory, and behavioral performance measures, and DZ administration, under the conditions used, provided no functional benefits following injury.