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

Abstract

Purpose: We recently showed that progesterone treatment can reduce lesion size and behavioral deficits after moderate-to-severe bilateral injury to the medial prefrontal cortex in immature male rats. Whether there are important sex differences in response to injury and progesterone treatment in very young subjects has not been given sufficient attention. Here we investigated progesterone's effects in the same model of brain injury but with pre-pubescent females.

Methods: Twenty-eight-day-old female Sprague-Dawley rats received sham (n = 14) or controlled cortical impact (CCI) (n = 21) injury, were given progesterone (8 mg/kg body weight) or vehicle injections on post-injury days (PID) 1-7, and underwent behavioral testing from PID 9-27. Brains were evaluated for lesion size at PID 28.

Results: Lesion size in vehicle-treated female rats with CCI injury was smaller than that previously reported for similarly treated age-matched male rats. Treatment with progesterone reduced the effect of CCI on extent of damage and behavioral deficits.

Conclusion: Pre-pubescent female rats with midline CCI injury to the frontal cortex have reduced morphological and functional deficits following progesterone treatment. While gender differences in susceptibility to this injury were observed, progesterone treatment produced beneficial effects in young rats of both sexes following CCI.

Fig 1. Lesion reconstruction analysis of juvenile female rats with controlled cortical impact (CCI) treated with progesterone (PROG) vs. vehicle.

Mean percent (± SEM) of volumetric tissue loss at 6 anterior-to-posterior (A/P) levels at 4 weeks post-injury. # = difference between the CCI+vehicle-treated group and CCI rats given 8 mg/kg PROG. Values are mean ± SEM (n = 6–11 / group).

Fig 2. Effect of progesterone (PROG) treatment on vestibulomotor function in female CCI rats treated with PROG vs. vehicle.

PROG (8 mg/kg) -treated CCI rats showed improvement in balancing and walking on the rotarod tasks. The Sham+PROG group was given 16-mg/kg doses of PROG. * = different from sham + vehicle; # = different from CCI + vehicle (p’s < 0.05). ‡ = different from baseline within each group. Values are mean ± SEM (n = 6–11).

Fig 3. Effects of progesterone (PROG) on learning and memory task as assessed by latency to locate the Morris water maze (MWM) platform.

During Run 1 (a) on the acquisition phase there was a significant effect of controlled cortical impact injury. Eight mg/kg PROG proved beneficial by decreasing the mean latency to find a hidden platform in the MWM compared to the CCI+vehicle-treated group. There was no clear effect of PROG treatment on Run 2 (b) or during the reversal phase (p > 0.05). The Sham+PROG group was given 16 mg/kg doses of PROG. * = different from Sham+Vehicle; # = different from CCI+Vehicle (p’s < 0.05). ‡ = different from baseline within each group; n = 6–11.

Fig 4. Tabulated comparative deficits between male and female controlled cortical impact injury.

Bold numbers with asterisk (*) indicate differences between treatment groups within the same gender, p < .05. Darker-shaded cells indicate where male rats either found the hidden MWM platform faster or made fewer visits to the closed arm of the EPM than similarly treated female rat pups (between-gender analysis), p < .05. Lighter-shaded cells indicate where female rat pups either weighed less, had smaller lesions, spent less time in the open arm of the EPM, tended to travel longer distances (Open Field), remained on the rotarod longer, or found the MWM platform faster than similarly treated male counterparts (b/w gender analysis), p < .05; PID 0 = day of injury but prior to surgery; PID -1 = day(s) before surgery; MWM: Morris Water Maze; CCI: controlled cortical impact; Mean +/- SEM; n = 6–11. Male data (columns 3, 5, 7, and 9) were previously published [26].