Table 2.

Neuroprotective effects of progesterone after traumatic brain injury (animal models).

Study	Animal Model	Animal Species	Progesterone Treatment Protocol	Primary End Points	Conclusions
Roof, 1996 [27]	Medial frontal cortex contusion by dynamic cortical deformation	Rats	Progesterone treatment 1h after injury	Brain edema	Progesterone effectively reduced brain edema when treatment was delayed until 24h after injury.
Wright, 2001 [29]	Bilateral medial frontal cortex injury	Rats	Progesterone (4 mg/kg), intraperitoneally at 1, 6, and 24 h post injury.	Brain edema	Progesterone significantly decreased cerebral edema after TBI in adult male rats.
Thomas, 1999 [56]	Spinal cord injury (Laminectomy with contusion)	Rats	Progesterone treatment	1. Functional status 2. Histologic analysis	Progesterone improved clinical and histologic outcomes compared with the control groups.
Allitt, 2015 [33]	Cortical impact acceleration-induced diffuse TBI.	Rats	Progesterone (P4) treatment	Short-term (4 days post-TBI) and long-term (8 weeks post-TBI) functional outcomes	Short-term: neural responses in supragranular layers were suppressed, and TBI-induced suppression in the granular and infragranular layers was reversed. Long-term: There were inconsistent effects of P4 on the TBI-induced hyperexcitation in supragranular layers.
Lopez-Rodriguez, 2015 [34]	Traumatic brain injury (weight-drop)	Mice	None	Correlation between levels of neuroactive steroids in the brain and plasma at 24h, 72h and 2w after injury and clinical outcomes.	Brain levels of progesterone, tetrahydro- progesterone, isopregnanolone and 17β-estradiol were decreased at 24h, 72h and 2w after TBI. Brain levels of progesterone and dehydroepiandrosterone showed a positive correlation with neurological recovery.
Peterson, 2015 [35]	Cortical contusion injury after craniotomy	Rats	Combination treatment of nicotinamide (NAM) and progesterone	1. Behavioral testing 2. Histological analysis of brain lesion	NAM and progesterone treatment resulted in significant improvements in recovery of function, and reduced lesion cavitation, degenerating neurons, and reactive astrocytes 24h after injury.
Nudi, 2015 [40]	Controlled cortical impact (medial frontal cortex)	Rats	10-mg/kg progesterone or vehicle injections 4h after injury and every 12h for 72 h after injury, followed by embryonic neural stem cells (eNSC) transplantation	Behavioral testing	Multimodal therapeutic approach after TBI improved functional recovery to a greater magnitude than either method alone.
Si, 2014 [42]	Traumatic brain injury (modified Feeney's weight-drop)	Rats	Progesterone treatment	1. Neurological outcomes 2. Histological analysis of the brain lesion	Progesterone treatment significantly reduced the post-injury inflammatory response, brain edema, and Evans blue dye extravasation, and improved neurological scores compared with control animals.
Xu, 2014 [43]	Surgical brain injury (SBI)	Rats	Low and high doses of progesterone vs. dexamethasone treatment	Histological analysis of the brain lesion	Progesterone reduced astrocyte and microglia responses, and attenuated brain edema with preservation of the blood brain barrier. Progesterone was as effective as dexamethasone in reducing brain edema and inflammation.
Geddes, 2014 [41]	Controlled cortical impact (CCI) model, pediatric model	Rats	4,8 and 16 mg/kg doses of progesterone treatment 7d after injury	Behavioral testing	Progesterone ameliorated the injury-induced neurological deficits.
Pascual, 2013 [44]	Traumatic brain injury after craniotomy	Mice	Progesterone treatment 16 mg/kg intraperitoneally	1. Neurological outcomes 2. Histological analysis of the brain lesion	Progesterone treatment reduced the size of the pericontusional lesion and blood brain barrier macromolecular leakage after TBI, and improved neurological outcomes.