Effects of 2,4-dinitrophenol on ischemia-induced blood-brain barrier disruption

Summary

This study examines the effect of 2,4-dinitrophenol (DNP), a mitochondrial uncoupling agent, during focal brain ischemia induced by middle cerebral artery (MCA) occlusion. Blood-brain barrier (BBB) disruption was assessed after 2 hours of occlusion with 2 hours of reperfusion or 4 hours of permanent occlusion by measurement of the influx rate constant (K_i) for ³H-inulin in the MCA territory ipsi- and contralateral to the occlusion. Three experimental groups were examined: vehicle and 1 and 5 mg/kg DNP treated animals (given 30 minutes prior to occlusion). Four hours of permanent MCA occlusion only induced a modest increase in the K_i for inulin in vehicle-treated animals (0.09 ± 0.01 vs. 0.07 ± 0.01 μL/g/min in contralateral tissue). Although 5 mg/kg DNP significantly increased this disruption (p < 0.01), this effect was relatively minor (0.14 ± 0.02 μL/g/min). In contrast, DNP treatment in transient ischemia markedly increased barrier disruption. The ipsilateral K_i for 3H-inulin were 0.15 ± 0.04, 0.37 ± 0.06, and 0.79 ± 0.17 μL/g/min in vehicle, 1 mg/kg DNP and 5 mg/kg DNP groups, respectively. DNP did not induce barrier disruption in the contralateral hemisphere. Thus, while there is evidence that DNP can be neuroprotective, it has adverse effects on the BBB during ischemia, particularly with reperfusion. Considering the importance of naturally- or therapeutically-induced reperfusion in limiting brain damage, this may limit the utility of DNP and mitochondrial uncouplers as therapeutic agents.