Robin L. Roof

Progesterone Facilitates Cognitive Recovery and Reduces Secondary Neuronal Loss Caused by Cortical Contusion Injury in Male Rats

The ability of progesterone to reduce the cerebral edema associated with traumatic brain damage first became apparent when we observed that males had significantly more edema than females after cortical contusion. In addition, edema was almost absent in pseudopregnant female rats, a condition in which progesterone levels are high relative to estrogen. Progesterone injections given after injury also reduced edema and were equally effective in both males and females. The present experiment was done to determine if the progesterone-induced reduction in edema could also prevent secondary neuronal degeneration and reduce the behavioral impairments that accompany contusion of the medial frontal cortex. Progesterone-treated rats were less impaired on a Morris water maze spatial navigation task than rats treated with the oil vehicle. Progesterone-treated rats also showed less neuronal degeneration 21 days after injury in the medial dorsal thalamic nucleus, a structure that has reciprocal connections with the contused area.

Progesterone protects against lipid peroxidation following traumatic brain injury in rats

The gonadal hormone, progesterone, has been shown to have neuroprotective effects in injured nervous system, including the severity of postinjury cerebral edema. Progesterones attenuation of edema is accompanied by a sparing of neurons from secondary neuronal death and with improvements in cognitive outcome. In addition, we recently reported that postinjury blood-brain barrier (BBB) leakage, as measured by albumin immunostaining, was significantly lower in progesterone treated than in nontreated rats, supporting a possible protective action of progesterone on the BBB. Because lipid membrane peroxidation is a major contributor to BBB breakdown, we hypothesized that progesterone limits this free radical-induced damage. An antioxidant action, neuroprotective in itself, would also account for progesterones effects on the BBB, edema, and cell survival after traumatic brain injury. To test progesterones possible antiperoxidation effect, we compared brain levels of 8-isoprostaglandin F2 alpha (8-isoPGF2 alpha), a marker of lipid peroxidation, 24, 48, and 72 h after cortical contusion in male rats treated with either progesterone or the oil vehicle. The brains of progesterone treated rats contained approximately one-third of the 8-isoPGF2 alpha found in oil-treated rats. These data suggest progesterone has antioxidant effects and support its potential as a treatment for brain injury.

Gender influences outcome of brain injury: progesterone plays a protective role

The contributions of gender and gonadal hormones in the cascade of events following brain injury are largely unexplored. We measured cerebral edema following cerebral contusion in rats under three hormonal conditions to address this issue. Normally cycling females exhibited significantly less edema than males, and pseudopregnant females were virtually spared from post-injury edema. Subsequent studies of ovariectomized females, with or without hormone treatment, indicated that the reduction of cerebral edema was associated primarily with the presence of circulating progesterone. We conclude that progesterone has a protective effect on the brain following traumatic injury.

Progesterone rapidly decreases brain edema : Treatment delayed up to 24 hours is still effective

Cerebral edema is a serious side effect of traumatic brain injury. We have previously established that progesterone injections, initiated within 1 h after cortical contusion injury, reduced edema when assessed 3 days later. To determine how rapidly progesterone can reduce edema, male and female rats were given the hormone 1 h after damage to the medial frontal cortex, and edema levels were assessed between 2 h and 7 days postinjury. Progesterone decreased edema with 6 h of the injury and continued to be effective for the duration of treatment. In addition, we assessed whether progesterone injections are effective when delays are imposed between injury and initiation of treatment. Male and female rats received progesterone after postinjury delays 6, 24, or 48 h. Progesterone was effective in reducing edema when treatment was delayed until 24 h after injury.

Gender differences in Morris water maze performance depend on task parameters

This study demonstrates that the relative performance of male and female rats on a Morris water maze task changes when the task parameters are varied. In three separate experiments, male and female rats were tested on a different variation of the Morris water maze. In all cases, on each of 10 days of testing, rats were given an initial trial in which the escape platform was randomly placed in a new position. A second trial was given one 1 h later. When the release position did not change between daily trials, no gender differences were observed. When the release position was changed between the initial and subsequent trial, females, but not males, showed reduced retention of the platform location on the second trial. This implies a male superiority for the task. However, a third manipulation of the task parameters demonstrated that females were as accurate and efficient as males at finding and remembering the platform location, even when released from a new position, as long as major landmark cues in the room remained constant. This study supports the hypothesis that male and female rats use different types of spatial cues when solving maze tasks, and stresses the importance of separating the effects of task variables from possible endogenous sender differences in ability.

Progesterone treatment attenuates brain edema following contusion injury in male and female rats.

To assess the effectiveness of progesterone as a treatment for edema following traumatic brain injury, male and female rats were injected with progesterone or the oil vehicle over a 3-day period following a cortical contusion injury. Oil-treated rats showed significant localized edema as measured by the wet weight/dry weight tissue punch technique. Progesterone-treated rats, both male and female, showed marked attenuation, or in some cases, absence of this post-injury edema. We conclude that progesterone shows promise as a treatment for edema following traumatic brain injury.

Gender-specific impairment on Morris water maze task after entorhinal cortex lesion.

After unilateral entorhinal cortex lesion, deficits on a working spatial memory Morris water maze task were examined in male and female rats to determine if gender differences exist in response to hippocampal deafferentation. Brain-damaged males showed a persistent water maze deficit that persisted throughout the 10 days of testing. Brain-damaged females did not. The performance of the injured females was only slightly impaired relative to sham males and females, and was significantly better than males with EC damage. This lack of a water maze deficit in lesion females is hypothesized to be due either to gender differences in sprouting responses or to a more flexible use of multiple cues by females relative to males.

A reliable and sensitive enzyme immunoassay method for measuring 8-isoprostaglandin F2α: a marker for lipid peroxidation after experimental brain injury

The objectives of this study were to determine (1) if levels of 8-isoprostaglandin F2 alpha (8-isoPGF2 alpha), a non-enzymatically produced prostaglandin, were increased after cortical contusion and (2) if enzyme immunoassay (EIA) could be used to quantify 8-isoPGF2 alpha levels. 24 h after the contusion there was a significant rise in 8-isoPGF2 alpha compared to control levels. The levels returned to baseline by 72 h postinjury. The results show that this EIA method is a reliable and sensitive technique for measuring brain lipid peroxidation.

Effects of unilateral entorhinal cortex lesion on retention of water maze performance

In a previous study, adult male Sprague-Dawley rats with unilateral, electrolytic entorhinal cortex lesions showed significant deficits in acquisition of a water maze task that measured working memory. The 10 days of testing used two trials per day with an intertrial interval of 1 h, and the rats with entorhinal damage were impaired in total distance to the platform in both trials. In the present retention study, rats who learned the same task prior to injury and were then retested for 5 days after lesion showed only a first day deficit in total distance to platform in the second trial. Analysis of swim patterns indicated that rats with unilateral entorhinal lesions used an altered strategy in retention testing to find the platform in the second trial of each day and incorporated the use of headings appropriate for Trial 1 only. This altered or compensatory strategy was not the optimum choice for problem solution. Although the rats then were able to switch headings and find the platform without significant impairment in total distance to platform on days 2-5 of testing, the use of an initial incorrect strategy indicated subtle residual deficits in cue integration and use of working memory.