Progesterone protects mitochondrial function in a rat model of pediatric traumatic brain injury.

Progesterone has been studied extensively in preclinical models of adult traumatic brain injury (TBI), and has advanced to clinical trials in adults with TBI. However, there are very few preclinical studies in pediatric TBI models investigating progesterone for neuroprotection. Immature male and female rats (postnatal day, PND 17-21) underwent controlled cortical impact (CCI) to the left parietal cortex. Rats received either progesterone (10 mg/kg) at 1 h (i.p.) and 6 h (s.c.) after TBI or vehicle (22.5 % cyclohexdrin), and were compared to naïve, age-matched littermates. At 24 h after CCI, brain mitochondria were isolated from the ipsilateral hemisphere. Active (State 3) and resting (State 4) mitochondrial respiration were measured, and mitochondrial respiratory control ratio (RCR, State 3/State 4) was determined. Total mitochonidral glutathione content was measured. A separate group of rats were studied for histology, and received progesterone or vehicle every 24 h (s.c.) for 7 days. In male rats, TBI reduced mitochondrial RCR, and progesterone preserved mitochondrial RCR. This improvement of RCR was predominantly through significant decreases in State 4 respiratory rates. In female rats, post-injury treatment with progesterone did not significantly improve mitochondrial RCR. Normal (uninjured) male rats had lower mitochondrial glutathione content than normal female rats. After TBI, progesterone prevented loss of mitochondrial glutathione in male rats only. Tissue loss was reduced in progesterone treated female rats at 7d after CCI. Future studies will be directed at correlation with neurologic outcome testing. These preclinical studies could provide information for planning future clinical trials of progesterone treatment in children with TBI.