Regular ArticleProgesterone Rapidly Decreases Brain Edema: Treatment Delayed up to 24 Hours Is Still Effective
Abstract
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 within 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 of 6, 24, or 48 h. Progesterone was effective in reducing edema when treatment was delayed until 24 h after injury.
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Sex differences in the effects of mild traumatic brain injury and progesterone treatment on anxiety-like behavior and fear conditioning in rats
2023, Experimental NeurologyMild traumatic brain injuries (mild TBIs) commonly occur in young adults of both sexes, oftentimes in high-stress environments. In humans, sex differences have been observed in the development of post-concussive anxiety and PTSD-like behaviors. Progesterone, a sex steroid that has neuroprotective properties, restores cognitive function in animal models following more severe TBI, but its effectiveness in preventing the psychological symptoms associated with mild TBI has not been evaluated. Using a model of mild TBI that pairs a social stressor (social defeat) with weight drop, male and naturally estrous-cycling female rats were treated with 4 mg/kg progesterone or vehicle once daily for 5 days after injury. Behavioral measures, including elevated plus maze (EPM), contextual fear conditioning, and novel object recognition (NOR) were assessed following progesterone treatment. Anxiety-like behavior was increased by mild TBI in male rats, with a smaller effect seen in female rats in the diestrus phase at the time of EPM testing. In contrast, mild TBI impaired fear learning in female rats in estrus at the time of fear acquisition. Progesterone treatment failed to attenuate post-mild TBI anxiety-like behavior in either sex. Furthermore, progesterone increased fear conditioning and impaired NOR discrimination in male rats, independent of TBI status. Overall, both sex and estrous cycle contributed to psychological outcomes following mild TBI, which were not ameliorated by post-TBI progesterone. This suggests sex steroids play an important role as a moderator of the expression of mild TBI-induced psychological symptoms, rather than as a potential treatment for their underlying etiology.
Comparing imaging biomarkers of cerebral edema after TBI in young adult male and female rats
2022, Brain ResearchTraumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Cerebral edema following TBI is known to play a critical role in injury severity and prognosis. In the current study we used multimodal magnetic resonance imaging (MRI) to assess cerebral edema 24 h after unilateral contusive TBI in male and female rats. We then directly quantified brain water content in the same subjects ex vivo. We found that both males and females had similarly elevated T2 values after TBI compared with sham controls. Apparent diffusion coefficient (ADC) was more variable than T2 and did not show significant injury effects in males or females. Brain water was elevated in male TBI rats compared with sham controls, but there was no difference between female TBI and sham groups. Notably, MRI biomarkers of edema were more closely correlated with brain water in male rats; female rats did not show any relationship between brain water and T2 or ADC. These observations raise questions about the interpretation of radiological findings traditionally interpreted as edema in female TBI patients. A better understanding of sex differences and similarities in the pathophysiology of post-traumatic edema is needed to help improve patient management and the development of effective treatment strategies for men and women.
Antioxidant therapies in traumatic brain injury
2022, Neurochemistry InternationalOxidative stress plays a crucial role in traumatic brain injury (TBI) pathogenesis. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) formed in excess after TBI synergistically contribute to secondary brain damage together with lipid peroxidation products (reactive aldehydes) and inflammatory mediators. Furthermore, oxidative stress, endoplasmic reticulum stress and inflammation potentiate each other. Following TBI, excessive oxidative stress overloads the endogenous cellular antioxidant system leading to cell death. To combat oxidative stress, several antioxidant therapies were tested in preclinical animal models of TBI. These include free radical scavengers, activators of antioxidant systems, Inhibitors of free radical generating enzymes and antioxidant enzymes. Many of these therapies showed promising outcomes including reduced edema, blood-brain barrier (BBB) protection, smaller contusion volume, and less inflammation. In addition, many antioxidant therapies also promoted better sensory, motor, and cognitive functional recovery after TBI. Overall, preventing oxidative stress is a viable therapeutic option to minimize the secondary damage and to improve the quality of life after TBI.
Acute progesterone injection has been shown to reduce brain edema following traumatic brain injury (TBI) due to its neuroprotective effect. We investigated the effects of sustained release of progesterone through implantation of subcutaneous capsules on rat's brain edema and alteration of cerebrospinal fluid (CSF), and serum ratio of NGF/IL-6 after TBI. This experiment was performed on ovariectomized (OVX) rats and the brain injury was induced by Marmarou's method. A high and a low dose of progesterone (HP and LP) was injected intraperitoneally two h after the brain injury. In addition, in the capsule progesterone-treated group (CP), the intervention was implemented 6 h after the brain injury. Brain edema, NGF and IL-6 biomarkers in serum and cerebrospinal fluid (CSF) were measured 48 h after the TBI in injection groups and one week after the TBI in the CP group. No significant difference was found in the two groups or in the admonition methods. After TBI, the NGF level increased and IL-6 level decreased by injection of both doses, as well as by taking the capsule. Ratio of NGF/IL-6 in CSF increased significantly by all forms of progesterone administration. The increase in the level of NGF and IL-6 after TBI was higher in CSF than in serum. These results indicated that effects of progesterone in capsule form were better than the injection form. Progesterone probably works by increasing NGF and reducing IL-6. Future studies should investigate the ratio of these biomarkers as a variable to determine the neuroprotective effects of another drug.
Traumatic Brain Injury
2020, Braddom's Physical Medicine and RehabilitationTraumatic brain injury (TBI), defined as a traumatic blow or jolt to the head, or penetrating trauma to the skull that injures the brain, is a worldwide epidemic that has a substantial impact on global health and function. In this chapter, we overview TBI epidemiology and health care costs as well as discuss the fundamental pathophysiology associated with primary and secondary injury. We discuss TBI across the injury severity spectrum and continuum of care and also in the context of other injury complex elements such as injury due to blast, hypoxic-ischemic brain injury, polytrauma, and shaken-baby syndrome. We discuss how TBI influences neurotransmission and the myriad of secondary symptoms, conditions, and complications that arise due to TBI. Key testing and medical management approaches are discussed, and the roles of rehabilitation team members across the continuum of care are outlined. Translational research perspectives, including biomarkers and imaging modalities, as well as community integration and TBI prevention strategies are discussed. This comprehensive overview of TBI provides up-to-date perspectives and the fundamental literature needed for rehabilitation clinicians to be knowledgeable and address TBI epidemiology, pathophysiology, secondary conditions, management, prognostication, outcome, community reintegration, and prevention. Pediatric perspectives on these areas as also provided.
The sex-specific interaction of the microbiome in neurodegenerative diseases
2019, Brain ResearchSeveral neurologic diseases exhibit different prevalence and severity in males and females, highlighting the importance of understanding the influence of biologic sex and gender. Beyond host-intrinsic differences in neurologic development and homeostasis, evidence is now emerging that the microbiota is an important environmental factor that may account for differences between men and women in neurologic disease. The gut microbiota is composed of trillions of bacteria, archaea, viruses, and fungi, that can confer benefits to the host or promote disease. There is bidirectional communication between the intestinal microbiota and the brain that is mediated via immunologic, endocrine, and neural signaling pathways. While there is substantial interindividual variation within the microbiota, differences between males and females can be detected. In animal models, sex-specific microbiota differences can affect susceptibility to chronic diseases. In this review, we discuss the ways in which neurologic diseases may be regulated by the microbiota in a sex-specific manner.
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To whom correspondence should be addressed at Department of Psychology, Texas Christian University, Fort Worth, TX 76129. Fax: (817) 921-7110.