Biomedical subjects

R L Roof

Publications and source records attributed to R L Roof.

15 recordsLinked to original sources

PubMed2001

A comparison of long-term functional outcome after 2 middle cerebral artery occlusion models in rats.

BACKGROUND AND PURPOSE: Proven behavioral assessment strategies for testing potential therapeutic agents in rat stroke models are needed. Few studies include tasks that demand higher levels of sensorimotor and cognitive function. Because behavioral outcome and rate of recovery vary among ischemia models, there is a need to characterize and compare performance on specific tasks across models. METHODS: To this end, sensorimotor and cognitive deficits were assessed during a 5-week period after either permanent proximal middle cerebral artery occlusion (pMCAO) or permanent distal middle cerebral artery occlusion combined with a 90-minute occlusion of both common carotid arteries (dMCAO/tCCAO) in Sprague-Dawley rats. The EBST, hindlimb and forelimb placing, and cylinder tests were given at regular intervals postinjury to assess sensorimotor function. Cognitive function was assessed with a multitrial water navigation task. RESULTS: pMCAO, which caused both striatal and cortical damage, produced persistent sensorimotor and cognitive deficits. Limb placing responses and postural reflexes were impaired throughout the month of testing. A persistent bias for using the ipsilateral forelimb for wall movements in the cylinder test was observed as well as a bias for landing on the opposite forelimb. pMCAO rats were also impaired in the water navigation task. dMCAO/tCCAO, which caused only cortical damage, produced similar sensorimotor deficits, but these were greatly diminished by 2 weeks after injury. No impairment was found for water tank navigation. Correlations between forelimb placing (both models), water navigation performance (pMCAO model), and sensorimotor asymmetry (dMCAOtCCAO model) and infarct volume were observed. CONCLUSIONS: Based on the range of functions affected and stability of observed deficits, the pMCAO model appears to be preferable to the dMCAO/tCCAO model for use in assessing therapeutic agents for stroke.

Animals↗

PubMed2000

Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats.

While a number of laboratories have begun to examine gender differences in outcome following experimental stroke, little is known about the relative response of male and female brains to traumatic injury. In the following series of experiments, we used the Marmarou impact-acceleration head injury model (with a 500-g, 1.5-m weight drop) to compare the pathophysiological responses of male and female rats to closed-head injury. Cortical blood flow (CBF; laser-doppler flowmetry), mean arterial blood pressure (MAP), blood gas levels, blood pH, and body temperature were measured preinjury and at regular intervals postinjury. Acute survival was assessed 1 h after injury. The role of estrogen in the observed gender differences was assessed by examining these physiological measures after injury in ovariectomized females, with or without 17beta-estradiol replacement, and in intact males, with or without exogenous 17beta-estradiol administration. In the first experiment, significantly more females (100%) survived the acute injury period (60 min) after injury than did males (72%). Survival appeared related to the magnitude and persistence of the posttraumatic drop in MAP. In a second experiment, females showed a less dramatic reduction in and better recovery of CBF than males. The gender difference in CBF was paralleled to some degree by differences in the pattern of MAP changes after injury. Differences in body weight, blood gas levels, or blood pH did not account for the gender difference in CBF. Postinjury CBF was higher in female and male rats given 2 weeks of daily 17beta-estradiol injections prior to injury compared to those given the vehicle only. However, 17beta-estradiol administration did not alter MAP, suggesting that the gender difference in CBF was not strictly due to MAP changes. Our findings suggest that estrogen plays a role in maintaining adequate cerebral perfusion in the acute period following closed-head injury. This protective mechanism may underlie the gender difference in acute survival observed in this study, and may help explain observations of better outcome in females than in males after brain injury. We conclude that CBF preservation is one mechanism by which estrogen is neuroprotective following traumatic brain injury. We hypothesize, based upon known effects of estrogen, that the beneficial microvascular effects of estrogen most likely involve a combination of endothelial nitric oxide synthase induction and an antioxidant effect.

Acceleration↗

PubMed2000

Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone.

Increasing evidence has demonstrated striking sex differences in the pathophysiology of and outcome after acute neurological injury. Lesser susceptibility to postischemic and posttraumatic brain injury in females has been observed in experimental models. Additional evidence suggests this sex difference extends to humans as well. The greater neuroprotection afforded to females is likely due to the effects of circulating estrogens and progestins. In fact, exogenous administration of both hormones has been shown to improve outcome after cerebral ischemia and traumatic brain injury in experimental models. The neuroprotection provided by periinjury administration of these hormones extends to males as well. The mechanisms by which estrogen and progesterone provide such neuroprotection are likely multifactorial, and probably depend on the type and severity of injury as well as the type and concentration of hormone present. Both genomic and nongenomic mechanisms may be involved. Estrogen's putative effects include preservation of autoregulatory function, an antioxidant effect, reduction of A beta production and neurotoxicity, reduced excitotoxicity, increased expression of the antiapoptotic factor bcl-2, and activation of mitogen activated protein kinase pathways. It is hypothesized that several of these neuroprotective mechanisms can be linked back to estrogen's ability to act as a potent chemical (i.e., electron-donating) antioxidant. Progesterone, on the other hand, has a membrane stabilizing effect that also serves to reduce the damage caused by lipid peroxidation. In addition, it may also provide neuroprotection by suppressing neuronal hyperexcitability. The following review will discuss experimental and clinical evidence for sex differences in outcome after acute brain trauma and stroke, review the evidence implicating estrogens and progestins as mediators of this neuroprotection following acute neurological injury, and finally, address the specific mechanisms by which these hormones may protect the brain following acute neurological injury.

Acute Disease↗

PubMed1999

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.

Animals↗

PubMed1997

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. Progesterone's 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 progesterone's effects on the BBB, edema, and cell survival after traumatic brain injury. To test progesterone's 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.

Animals↗

PubMed1996

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.

Animals↗

PubMed1996

A reliable and sensitive enzyme immunoassay method for measuring 8-isoprostaglandin F2 alpha: 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.

Animals↗

PubMed1995

Blood-brain barrier breakdown and edema formation following frontal cortical contusion: does hormonal status play a role?

The present experiment was designed to evaluate and correlate the time course of blood-brain barrier (BBB) integrity and cerebral edema in adult male rats given medial frontal cortex contusions. The effect of sex hormones on BBB integrity in the same injury model was also examined, because previous work has shown that progesterone can reduce cerebral edema (Roof et al., 1993). BBB breakdown was assessed by Evans blue extravasation and albumin immunostaining while edema formation was measured by the wet weight dry weight technique. These processes were examined beginning 2 h and continuing up to 10 days after injury. Our findings show that medial frontal contusion in rats produces changes in cerebral water content and opening of the BBB that endures at least 7 days postinjury. Although pseudopregnancy has been shown to reduce cerebral edema at day 1 postinjury, we did not find any evidence that this hormonal state is associated with BBB repair.

Animals↗

PubMed1994

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.

Analysis of Variance↗

PubMed1993

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.

Animals↗

PubMed1993

The dentate gyrus is sexually dimorphic in prepubescent rats: testosterone plays a significant role.

In a morphological examination of the hippocampal formation of pre-pubescent rats, a testosterone-related sexual dimorphism was observed. The dentate gyrus granule cell layer was greater (8-9%) in width and length and laterally asymmetrical in males and in testosterone-treated females. This dimorphism was previously observed in adult rats. These data demonstrate that the dimorphism exists prior to puberty and is therefore not dependent on hormone changes associated with this event. In addition, a correlation between the size of this cell layer and performance on a spatial task were observed.

Animals↗

PubMed1993

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.

Animals↗

PubMed1993

Neonatal exogenous testosterone modifies sex difference in radial arm and Morris water maze performance in prepubescent and adult rats.

To study the involvement of testosterone in the development of spatial abilities, testosterone propionate (TP) was administered to male and female rats during the first week after birth. As adults, these rats were trained and tested on the radial arm maze (RAM) or the Morris water maze (MWM). Sex and neonatal TP treatment influenced number of trials to criterion, accuracy, and the use of an adjacent-arm strategy on the RAM, as well as the speed with which the rats learned the location of a hidden platform in the MWM. On both RAM and MWM, control males performed better than control females, but TP treatment reversed this pattern, producing better maze performance in females and worse in males. Neonatal TP effects on MWM performance were also examined in 21-day-old male and female rats. Performance paralleled that of the adults in all but the testosterone-treated male group, which did not differ from control males. The results of this study provide support for the hypothesis that circulating testosterone during brain development may play a role in the development of spatial memory, and suggest that, in the rat, both the sex difference and testosterone influence are present early in life.

Aging↗

PubMed1992

Testosterone improves maze performance and induces development of a male hippocampus in females.

In a combined behavioral and morphometric study, we observed a testosterone-related sexual dimorphism in the granule cell layer of the hippocampus of Sprague-Dawley rats that appears to be related to sex differences in spatial performance. This cell layer was larger and laterally asymmetrical in males. Neonatal testosterone treatment of females resulted in a more male-like hippocampus. These treated females also performed better than controls, and as well as males, on a spatial navigation task. In addition, a strong correlation between the size of granule cell layers and maze performance was detected.

Animals↗

PubMedDate not supplied

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.

Animals↗