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Progesterone protects mitochondrial function in a rat model of pediatric traumatic brain injury
Courtney L Robertson1, Manda Saraswati
1Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 1800 Orleans Street, Bloomberg Children's Center Room 6321, Baltimore, MD, 21287, USA, crober48@jhmi.edu.
Insights
Progesterone protected mitochondria in male rats after traumatic brain injury (TBI) by preserving respiratory control. In female rats, progesterone reduced tissue loss following TBI.
Area of Science:
- Neuroscience
- Biochemistry
- Pediatric Traumatic Brain Injury Research
Background:
- Progesterone is studied in adult TBI but lacks preclinical pediatric research.
- Pediatric TBI presents unique neurodevelopmental challenges.
- Investigating progesterone's neuroprotective effects in immature models is crucial.
Purpose of the Study:
- To investigate the neuroprotective effects of progesterone in a pediatric model of traumatic brain injury (TBI).
- To assess progesterone's impact on mitochondrial function and glutathione levels in immature male and female rats post-TBI.
- To evaluate progesterone's efficacy in reducing tissue loss in a pediatric TBI model.
Main Methods:
- Immature rats (PND 17-21) underwent controlled cortical impact (CCI).
- Progesterone or vehicle was administered post-injury.
- Mitochondrial respiration (State 3, State 4, RCR) and glutathione content were measured.
- Histology assessed tissue loss at 7 days post-CCI.
Main Results:
- In male rats, TBI reduced mitochondrial respiratory control ratio (RCR); progesterone preserved RCR by decreasing State 4 respiration.
- Progesterone prevented the loss of mitochondrial glutathione in male rats post-TBI.
- In female rats, progesterone did not significantly improve mitochondrial RCR but reduced tissue loss at 7 days post-CCI.
- Normal male rats had lower baseline mitochondrial glutathione than normal females.
Conclusions:
- Progesterone demonstrates sex-specific neuroprotective effects in a pediatric TBI model, primarily preserving mitochondrial function in males.
- Progesterone shows potential for reducing tissue damage in females post-TBI.
- These findings support further investigation into progesterone for clinical trials in pediatric TBI.
Abstract:
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.
