Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental braininjury

Object. Determining the efficacy of a drug used in experimental traumatic b rain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variabi lity, requiring relatively large sample sizes, and administration of the te sts themselves is also very time consuming. The authors previously demonstr ated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobeha vioral endpoints, it might prove useful as an outcome measure to establish therapeutic rime windows and dose-response curves in preclinical drug testi ng. This idea was tested in a model of TBI in rats. Methods. Animals treated with the selective N-type voltage-sensitive calciu m channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cort ical impact displayed significant improvement in brain mitochondrial functi on. When a single intravenous bolus injection of 4 mg/kg Ziconotide was giv en at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points , but more so between 2 and 6 hours postinjury. The authors evaluated the e ffects on mitochondrial function of Ziconotide at different doses by admini stering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, an d found 4 mg/kg to be the optimum dose. Conclusions. The authors established these time-window profiles and dose-re sponse curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Est ablishing similar time-window profiles and dose-response curves by using ne urobehavioral endpoints would have required using 114 rats in much more ela borate experiments.