OBJECT: Determining the efficacy of a drug used in experimental traumatic brain 
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 variability, requiring 
relatively large sample sizes, and administration of the tests themselves is 
also very time consuming. The authors previously demonstrated that experimental 
TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial 
dysfunction is easy to assess compared with neurobehavioral endpoints, it might 
prove useful as an outcome measure to establish therapeutic time windows and 
dose-response curves in preclinical drug testing. This idea was tested in a 
model of TBI in rats.
METHODS: Animals treated with the selective N-type voltage-sensitive calcium 
channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical 
impact displayed significant improvement in brain mitochondrial function. When a 
single intravenous bolus injection of 4 mg/kg Ziconotide was given 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 effects on mitochondrial 
function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a 
single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum 
dose.
CONCLUSIONS: The authors established these time-window profiles and 
dose-response curves on the basis of mitochondrial outcome measures in a total 
of 42 rats because there were such low standard deviations in these tests. 
Establishing similar time-window profiles and dose-response curves by using 
neurobehavioral endpoints would have required using 114 rats in much more 
elaborate experiments.