Progesterone Treatment Shows Benefit in a Pediatric Model of Moderate to Severe Bilateral Brain Injury

Abstract

PurposeControlled cortical impact (CCI) models in adult and aged Sprague-Dawley (SD) rats have been used extensively to study medial prefrontal cortex (mPFC) injury and the effects of post-injury progesterone treatment, but the hormone's effects after traumatic brain injury (TBI) in juvenile animals have not been determined. In the present proof-of-concept study we investigated whether progesterone had neuroprotective effects in a pediatric model of moderate to severe bilateral brain injury.MethodsTwenty-eight-day old (PND 28) male Sprague Dawley rats received sham (n = 24) or CCI (n = 47) injury and were given progesterone (4, 8, or 16 mg/kg per 100 g body weight) or vehicle injections on post-injury days (PID) 1–7, subjected to behavioral testing from PID 9–27, and analyzed for lesion size at PID 28.ResultsThe 8 and 16 mg/kg doses of progesterone were observed to be most beneficial in reducing the effect of CCI on lesion size and behavior in PND 28 male SD rats.ConclusionOur findings suggest that a midline CCI injury to the frontal cortex will reliably produce a moderate TBI comparable to what is seen in the adult male rat and that progesterone can ameliorate the injury-induced deficits.

Evaluating the neurotherapeutic potential of a water-soluble progesterone analog after traumatic brain injury in rats

“…Behavioral outcome measures are essential to this purpose. PROG has been shown to promote functional recovery in different brain injury models including stroke and TBI (Djebaili et al, 2004;Gibson and Murphy, 2004;Grossman et al, 2004;Gibson et al, 2005;Chen et al, 2007;Wali et al, 2011;Tang et al, 2013;Geddes et al, 2014;Robertson and Saraswati, 2014;Wali et al, 2014;Yousuf et al, 2014a,b;Peterson et al, 2015). Our results in the present study show that besides reducing the water content in the penumbral region at one day after TBI, EIDD-1723 significantly improved functional recovery and reduced accumulation of astrocytes and microglia, cells associated with post-injury inflammatory processes that can impair recovery of function.…”

Progesterone Effects in the Nervous System

“…In one study, Trotter and coworkers showed that the application of progesterone immediately after birth in infants with extremely low weight improved the neurological developmental outcome (Trotter et al, ). Consistent with this, two animal studies with juvenile rats treated with progesterone after induced TBI showed an improved neuronal outcome (Geddes et al, ; Robertson and Saraswati, ). The first study focused on behavioral tests and the analysis of lesion size after bilateral brain injury.…”

“…The first study focused on behavioral tests and the analysis of lesion size after bilateral brain injury. It was found that doses of 8 and 16 mg/kg progesterone resulted in a lower lesion size and a better behavioral outcome after TBI (Geddes et al, ).…”

Progesterone Treatment Shows Benefit in Female Rats in a Pediatric Model of Controlled Cortical Impact Injury

“…Anesthesia levels were monitored closely throughout surgery and were frequently adjusted between 400–700 mmHg/min, based on heart rate and oxygen saturation. In our previous study [ 26 ] we found that a 4.0-mm diameter stainless steel impactor resulted in a survivable, severe CCI injury in 28-day-old male rats so we used the same CCI parameters for the age-matched female rats.…”

“…Robertson et al [ 25 ] reported that tissue loss was reduced in PROG-treated female rats at 7d after unilateral contusion injury to the exposed brain and suggested a need for future studies looking at functional outcome measures. Recently, we showed that PROG treatment reduced lesion size and behavioral deficits after moderate-to-severe bilateral injury to the medial prefrontal cortex (mPFC) in post-natal day (PND) 28 male Sprague-Dawley (SD) rats [ 26 ]. Here we report on the response of pre-pubescent female rats with a similar TBI to post-injury PROG treatment.…”