Etoposide induced blood-brain barrier disruption in rats: duration of opening and histological sequelae

The intracarotid infusion of the antineoplastic compound etoposide enhances blood-brain barrier (BBB) permeability. In a rat model system, the functional reversibility and anatomic sequelae of etoposide induced BBB disruption were investigated. Etoposide, in a dose range from 3.0 to 22.5 mg/kg, was infused into the left internal carotid artery of Sprague-Dawley rats. BBB disruption was evaluated by the appearance in the infused hemisphere of systemically administered Evans blue dye and quantitatively by the ratio of counts of the technetium labeled chelate of diethylenetriaminepentaacetic acid in the infused to the noninfused hemisphere. Functional reversibility of altered BBB permeability was investigated at three dose levels of etoposide (3.0, 15.0, and 22.5 mg/kg) by the administration of Evans blue dye at the time of etoposide infusion and the administration of the technetium labeled chelate of diethylenetriamine-pentaacetic acid at varying time intervals after etoposide infusion. Fourteen groups of 12 rats each were studied to define the time course of altered BBB permeability at these three doses. The anatomic sequelae of etoposide induced BBB disruption were investigated at varying time intervals (up to 3 weeks) after intracarotid etoposide infusion. Nineteen rats were examined after sacrifice by intracardiac fixation perfusion with 10% formalin. Each brain was sectioned coronally and examined under light microscopy after hematoxylin and eosin staining. Evidence of BBB disruption was seen at all dose levels of etoposide. The degree of BBB disruption increased with increasing doses of etoposide. The duration of altered BBB permeability increased from less than 1 day at 3.0 mg/kg to between 3 and 4 days at 22.5 mg/kg. Histological studies revealed no evidence of parenchymal damage, although at 4 days postdisruption, a mild perivascular lymphocytic infiltration was noted in the infused hemisphere. Etoposide infusion and subsequent BBB disruption were well tolerated by all test animals. In a rat model system the intracarotid infusion of etoposide is capable of producing prolonged reversible BBB disruption.