Progesterone Improves Acute Recovery after Traumatic Brain Injury in the Aged Rat

Abstract

Recent evidence has demonstrated that treatment with progesterone can attenuate many of the pathophysiological events following traumatic brain injury (TBI) in young adult rats, but this effect has not been investigated in aged animals. In this study, 20-month-old male Fischer 344 rats with bilateral contusions of the frontal cortex (n = 4 per group) or sham operations received 8, 16, or 32 mg/kg of progesterone or vehicle. Locomotor activity was measured at 72 h to assess behavioral recovery. Brain tissue was harvested at 24, 48, and 72 h, and Western blotting was performed for inflammatory and apoptotic factors. Edema was assessed at 48 h by measuring brain water content. Injured animals treated with 8 and 16 mg/kg progesterone showed decreased expression of COX-2, IL-6, and NFkappaB at all time points, indicating a reduction in the acute inflammatory process compared to vehicle. The 16 mg/kg group also showed reduced apoptosis at all time points as well as decreased edema and improved locomotor outcomes. Thus, in aged male rats, treatment with 16 mg/kg progesterone improves short-term motor recovery and attenuates edema, secondary inflammation, and cell death after TBI.

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

“…The current findings, demonstrating progesterone's ability to regulate the DNA damage response, cell proliferation, and blood vessel remodeling following TBI, are novel and have not been previously described. The decreased dosedependent effect of progesterone on functional recovery and inflammatory markers in experimental TBI models (Cutler et al, 2007;Goss et al, 2003) is consistent with our findings of a decreased effect on gene expression at the higher dose of progesterone 7 days post-TBI. Currently, it is not known whether high-dose progesterone is more beneficial than lowdose progesterone at 7 days.…”

“…It was found that the 8 and 16 mg/kg doses improved water maze performance compared to the 32 mg/ kg dose, and that none of the doses significantly decreased lesion size (Goss et al, 2003). Similarly, a study in older rats also found that the 32 mg/kg dose resulted in significantly fewer beneficial effects on inflammatory factors than 8 mg/kg and 16 mg/kg at 48 h post-injury (Cutler et al, 2007).…”

Traumatic Brain Injury Causes Long-Term Reduction in Serum Growth Hormone and Persistent Astrocytosis in the Cortico-Hypothalamo-Pituitary Axis of Adult Male Rats

“…Rats were subjected to sham surgeries (n ¼ 4) or TBI (n ¼ 5) according to procedures described elsewhere (Cutler et al, 2007). Briefly, the rats were initially anesthetized under 5% isoflurane anesthesia for 3 min, 45 s, and nitrous oxide (700 mmHg=min) with oxygen (400 mmHg=min) as a carrier.…”

“…Briefly, the protein concentration in the supernatant was measured using Coomassie blue reagent, and the Cx, HT, and AP (not SME) homogenates were used to prepare the samples for SDS-PAGE, as described elsewhere (Cutler et al, 2007), to a final concentration of 1.2 mg=mL. AP Western samples with a concentration of 0.12 mg=mL were used for the assay of GH.…”

A Clinical Trial of Progesterone for Severe Traumatic Brain Injury

“…Multifactorial effects of progesterone include inhibition of inflammatory cytokines, reduced levels of inflammation-related factors, prevention of excitotoxicity, reduction of apoptosis, and control of vasogenic edema. [7][8][9][10] The progesterone receptor plays a key role in these neuroprotective effects. 11 A total of 20 research groups working with four species and 22 different models have found neuroprotective effects of progesterone in more than 180 experimental pharmacologic studies.…”