Publications by authors named "Farida Sohrabji"

61 Publications

New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases.

Front Aging Neurosci 2021 28;13:623751. Epub 2021 Jan 28.

Unidad de Investigación Neurovascular, Departamento Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid, Spain.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.
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http://dx.doi.org/10.3389/fnagi.2021.623751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876251PMC
January 2021

New directions in behavioral neuroscience: Sometimes old is new.

Neurosci Biobehav Rev 2021 06 4;125:108-109. Epub 2021 Feb 4.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University, Bryan, TX, USA.

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http://dx.doi.org/10.1016/j.neubiorev.2021.02.001DOI Listing
June 2021

Sex differences in stroke outcome correspond to rapid and severe changes in gut permeability in adult Sprague-Dawley rats.

Biol Sex Differ 2021 Jan 15;12(1):14. Epub 2021 Jan 15.

Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University-Health, 8447 Riverside Pkwy, Bryan, TX, 77807, USA.

Background: Sex differences in experimental stroke outcomes are well documented, such that adult males have a greater infarct volume, increased stroke-induced mortality, and more severe sensory-motor impairment. Based on recent evidence that the gut is an early responder to stroke, the present study tested the hypothesis that sex differences in stroke severity will be accompanied by rapid and greater permeability of the gut-blood barrier and gut dysbiosis in males as compared to females.

Method: Male and female Sprague-Dawley rats (5-7 months of age) were subject to endothelin (ET)-1-induced middle cerebral artery occlusion (MCAo). Sensory-motor tests were conducted pre- and 2 days after MCAo. Gut permeability was assessed in serum samples using biomarkers of gut permeability as well as functional assays using size-graded dextrans. Histological analysis of the gut was performed with H&E staining, periodic acid-Schiff for mucus, and immunohistochemistry for the tight junction protein, ZO-1. Fecal samples obtained pre- and post-stroke were analyzed for bacterial taxa and short-chain fatty acids (SCFAs).

Results: After stroke, males displayed greater mortality, worse sensory-motor deficit, and higher serum levels of proinflammatory cytokines IL-17A, MCP-1, and IL-5 as compared to females. MCAo-induced gut permeability was rapid and severe in males as indicated by dextran extravasation from the gut to the blood in the hyperacute (< 2 h) and early acute (2 days) phase of stroke. This was accompanied by dysmorphology of the gut villi and dysregulation of the tight junction protein ZO-1 in the acute phase. Fecal 16s sequencing showed no differences in bacterial diversity in the acute phase of stroke. Predictive modeling indicated that markers of gut permeability were associated with acute sensory-motor impairment and infarct volume.

Conclusions: These data show that extensive leakiness of the gut barrier is associated with severe post-stroke disability and suggest that reinforcing this barrier may improve stroke outcomes.
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http://dx.doi.org/10.1186/s13293-020-00352-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811247PMC
January 2021

Mir363-3p Treatment Attenuates Long-Term Cognitive Deficits Precipitated by an Ischemic Stroke in Middle-Aged Female Rats.

Front Aging Neurosci 2020 29;12:586362. Epub 2020 Sep 29.

Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Texas A&M University, Bryan, TX, United States.

Cognitive impairment and memory loss are commonly seen after stroke and a third of patients will develop signs of dementia a year after stroke. Despite a large number of studies on the beneficial effects of neuroprotectants, few studies have examined the effects of these compounds/interventions on long-term cognitive impairment. Our previous work showed that the microRNA mir363-3p reduced infarct volume and sensory-motor impairment in the acute stage of stroke in middle-aged females but not males. Thus, the present study determined the impact of mir363-3p treatment on stroke-induced cognitive impairment in middle-aged females. Sprague-Dawley female rats (12 months of age) were subjected to middle cerebral artery occlusion (MCAo; or sham surgery) and injected (iv) with mir363-3p mimic (MCAo + mir363-3p) or scrambled oligos (MCAo + scrambled) 4 h later. Sensory-motor performance was assessed in the acute phase (2-5 days after stroke), while all other behaviors were tested 6 months after MCAo (18 months of age). Cognitive function was assessed by the novel object recognition test (declarative memory) and the Barnes maze (spatial memory). The MCAo + scrambled group showed reduced preference for a novel object after the stroke and poor learning in the spatial memory task. In contrast, mir363-3p treated animals were similar to either their baseline performance or to the sham group. Histological analysis showed significant deterioration of specific white matter tracts due to stroke, which was attenuated in mir363-3p treated animals. The present data builds on our previous finding to show that a neuroprotectant can abrogate the long-term effects of stroke.
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http://dx.doi.org/10.3389/fnagi.2020.586362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550720PMC
September 2020

Gonadal hormones and stroke risk: PCOS as a case study.

Front Neuroendocrinol 2020 07 5;58:100853. Epub 2020 Jul 5.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Bryan, TX 77807, USA. Electronic address:

It is well known that stroke incidence and outcome is sex-dependent and influenced by age and gonadal hormones. In post-menopausal and/or aged females, declining estrogen levels increases stroke risk. However, women who experience early menopause also have an increase in stroke risk. This suggests that, regardless of age, gonadal hormones regulate stroke risk and severity. This review discusses prolonged gonadal hormone dysfunction in a common female endocrine disorder known as polycystic ovarian syndrome, PCOS, and the associated increased risk of stroke due to resulting hyperandrogenism and metabolic comorbidities.
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http://dx.doi.org/10.1016/j.yfrne.2020.100853DOI Listing
July 2020

Sex differences in stroke co-morbidities.

Exp Neurol 2020 10 23;332:113384. Epub 2020 Jun 23.

Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M HSC College of Medicine, Bryan, TX 77807, USA; Texas A&M Institute for Neuroscience, College Station, TX 77840, USA. Electronic address:

Males and females possess distinct biological differences that manifest in diverse risk profiles for acute and chronic diseases. A well-documented example of this is ischemic stroke. It has been demonstrated that older females have greater prevalence of, and worse outcome after, ischemic stroke than do males and younger females. Loss of estrogen after menopause is heavily implicated as a contributing factor for this phenomenon; however, there is mounting evidence to suggest that certain risk factors tend to occur more often in older females, such as hypertension and atrial fibrillation, while others more adversely affect females than they do males, such as diabetes and smoking. Sex-specific risk factors, such as oral contraceptive use and menopause, could also contribute to the discrepancy in stroke prevalence and outcome. Additionally, there is evidence to suggest that females tend to present with more nontraditional symptoms of acute stroke than do males, making it more difficult for clinicians to correctly identify the occurrence of a stroke, which may delay the administration of thrombolytic intervention. Finally, certain sociodemographic factors, such as the fact that females were more likely to live alone prior to stroke, may contribute to poorer recovery in females. This review will explore the various co-morbidities and sociodemographic factors that contribute to the greater prevalence of and poorer outcome after stroke in older females and will highlight the critical need for considering sex as a predisposing biological variable in stroke studies.
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http://dx.doi.org/10.1016/j.expneurol.2020.113384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418167PMC
October 2020

Reproductive Senescence and Ischemic Stroke Remodel the Gut Microbiome and Modulate the Effects of Estrogen Treatment in Female Rats.

Transl Stroke Res 2020 08 16;11(4):812-830. Epub 2019 Dec 16.

Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA.

Our previous work has shown that reproductively senescent (or middle-aged; 10-12-month-old) Sprague-Dawley female rats, that are naturally estrogen-deficient, have worse stroke outcomes as compared to normally estrous-cycling adult (5-6-month-old) females. Paradoxically, estrogen replacement to this middle-aged group exacerbates stroke outcomes, while it is neuroprotective in adult females. Recent studies reveal an important role for the gut microbiome and gut metabolites in cardiovascular health, including stroke outcomes. To determine whether gut dysbiosis underlies stroke severity in reproductive senescent females, and underlies the anomalous effects of estrogen on stroke, we compared the gut microbiota and gut metabolites pre and post stroke in (a) gonadally intact adult and middle-aged females, (b) in ovariectomized and estrogen-treated (OVX+E) adult and OVX+E middle-aged females, and (c) in middle-aged OVX+E females after fecal microbiome transfer. Our data show significant gut dysbiosis in reproductive senescent females at baseline and after stroke as indicated by an elevated ratio of the major phyla, Firmicutes/Bacteroidetes (F:B), reduced alpha diversity, and significant shifts in beta diversity as compared with adult females. Specific bacterial families were also altered as a result of reproductive aging, as well as gut metabolites, including elevated serum endotoxin levels and decreased short-chain fatty acids (SCFAs), with a concomitant increase in IL-17A, indicating that reproductive senescence significantly affects gut communities under pathologic conditions. Despite the differences in gonadally intact adult and middle-aged females, estrogen-treated ovariectomized (OVX+E) females of either age group displayed no differences in the major phyla, but there was increased abundance in specific bacterial taxa, including Prevotella and Lactobacillus. The SCFA butyrate was significantly reduced at baseline in the middle-aged OVX+E females, while circulating endotoxin LPS were elevated in this group after stroke, suggesting that gut metabolites were differently affected by estrogen treatment in the two age groups. A fecal transfer from adult OVX+E females to middle-aged OVX+E females significantly reduced infarct volume, improved behavioral recovery and transiently reduced IL-17A expression. These data provide the first evidence that microbial gut communities and metabolites are altered by reproductive senescence in female rats at baseline and after stroke, and suggest that estrogen may impact stroke recovery differently in adult and reproductive senescent females due to an age-specific effect on gut microbiota and metabolites.
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http://dx.doi.org/10.1007/s12975-019-00760-5DOI Listing
August 2020

The promises and pitfalls of sex difference research.

Front Neuroendocrinol 2020 01 16;56:100817. Epub 2019 Dec 16.

Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M HSC College of Medicine, Bryan, TX 77807, United States.

Funding agencies in North America and Europe are recognizing the importance of the integration of sex differences into basic and clinical research. Although these mandates are in place to improve our knowledge of health for both men and women, there have been a number of implementation issues that require vigilance on the part of funders and the research community. Here we discuss issues on simple inclusion of both sexes in studies to specialisation of sex differences with attention paid to statistics and the need for sex-specific treatments. We suggest differing mandates need to be considered regarding simple integration versus the need for studies in the specialisation of sex differences and/or the need for research that recognises the importance of male-specific or female-specific factors that influence subsequent health such as menstruation, menopause or pregnancy.
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http://dx.doi.org/10.1016/j.yfrne.2019.100817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050281PMC
January 2020

Age and sex differences in post-ischemic outcome and therapy.

Neurochem Int 2019 07 22;127:104472. Epub 2019 May 22.

Women's Health in Neuroscience Program, Department of Neuroscience & Experimental Therapeutics, Texas A&M Health Science Center, Bryan, TX, USA.

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http://dx.doi.org/10.1016/j.neuint.2019.104472DOI Listing
July 2019

Sex hormones and stroke: Beyond estrogens.

Horm Behav 2019 05 20;111:87-95. Epub 2018 Nov 20.

Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, TX 77807, United States of America.

Stroke risk and poor stroke outcomes in postmenopausal women have usually beeen attributed to decreased levels of estrogen. However, two lines of evidence suggest that this hormone may not be solely responsible for elevated stroke risk in this population. First, the increased risk for CVD and stroke occurs much earlier than menopause at a time when estrogen levels are not yet reduced. Second, estrogen therapy has not successfully reduced stroke risk in all studies. Other sex hormones may therefore also contribute to stroke risk. Prior to menopause, levels of the gonadotrophin Follicle Stimulating Hormone (FSH) are elevated while levels of the gonadal peptide inhibin are lowered, indicating an overall decrease in ovarian reserve. Similarly, reduced estrogen levels at menopause significantly increase the ratio of androgens to estrogens. In view of the evidence that androgens may be unfavorable for CVD and stroke, this elevated ratio of testosterone to estrogen may also contribute to the postmenopause-associated stroke risk. This review synthesizes evidence from different clinical populations including natural menopause, surgical menopause, women on chemotherapy, and preclinical stroke models to dissect the role of ovarian hormones and stroke risk and outcomes.
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http://dx.doi.org/10.1016/j.yhbeh.2018.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527470PMC
May 2019

Morphine increases macrophages at the lesion site following spinal cord injury: Protective effects of minocycline.

Brain Behav Immun 2019 07 23;79:125-138. Epub 2019 Jan 23.

Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, United States. Electronic address:

Opioids are among the most effective and widely prescribed medications for the treatment of pain following spinal cord injury (SCI). Spinally-injured patients receive opioids within hours of arrival at the emergency room, and prolonged opioid regimens are often employed for the management of post-SCI chronic pain. However, previous studies in our laboratory suggest that the effects of opioids such as morphine may be altered in the pathophysiological context of neurotrauma. Specifically, we have shown that morphine administration in a rodent model of SCI increases mortality and tissue loss at the injury site, and decreases recovery of motor and sensory function, and overall health, even weeks after treatment. The literature suggests that opioids may produce these adverse effects by acting as endotoxins and increasing glial activation and inflammation. To better understand the effects of morphine following SCI, in this study we used flow cytometry to assess immune-competent cells at the lesion site. We observed a morphine-induced increase in the overall number of CD11b+ cells, with marked effects on microglia, in SCI subjects. Next, to investigate whether this increase in the inflammatory profile is necessary to produce morphine's effects, we challenged morphine treatment with minocycline. We found that pre-treatment with minocycline reduced the morphine-induced increase in microglia at the lesion site. More importantly, minocycline also blocked the adverse effects of morphine on recovery of function without disrupting the analgesic efficacy of this opioid. Together, our findings suggest that following SCI, morphine may exacerbate the inflammatory response, increasing cell death at the lesion site and negatively affecting functional recovery.
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http://dx.doi.org/10.1016/j.bbi.2019.01.023DOI Listing
July 2019

Mir363-3p attenuates post-stroke depressive-like behaviors in middle-aged female rats.

Brain Behav Immun 2019 05 10;78:31-40. Epub 2019 Jan 10.

Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University, Bryan, TX 77807, United States. Electronic address:

Women are more likely to develop Post Stroke Depression (PSD) than men and generally do not respond well to anti-depressants with age. This study investigated the effect of microRNA mir363-3p treatment on PSD using a physiologically-relevant animal model. Our previous work showed that mir363-3p treatment, delivered post-stroke, effectively reduces infarct volume in the acute phase of stroke in middle-aged females but not males. Middle-aged female Sprague Dawley rats were tested for baseline sensory motor function and depressive-like behaviors, and then subjected to ischemic stroke via middle cerebral artery occlusion (MCAo) or sham surgery. Animals received either control oligos (MCAo+scrambled, Sham+scrambled) or mir363-3p (MCAo+mir363-3p, Sham+mir363-3p) treatment 4 h later. Sensory motor function and depressive-like behaviors were reassessed up to 100 d after stroke, and circulating levels of IL-6, TNF-alpha and Brain-Derived Neurotrophic Factor (BDNF) were quantified at regular intervals. Prior to termination, Fluorogold was injected into the striatum to assess meso-striatal projections. MCAo+scrambled animals had impaired sensorimotor performance in the acute phase (5 days) of stroke and developed anhedonia, decreased sociability and increased helplessness in the chronic phase. MCAo+mir363-3p animals showed significantly less sensory motor impairment and fewer depressive-like behaviors. IL-6 and TNF-alpha were elevated transiently at 4 weeks after MCAo in both groups. BDNF levels decreased progressively after stroke in the MCAo+scrambled group, and this was attenuated in the mir363-3p group. The number of retrogradely-labeled SNc and VTA cells was reduced in the ischemic hemisphere of the MCAo+scrambled group. In contrast, there was no interhemispheric difference in the number of retrogradely-labeled SNc and VTA cells of MCAo+mir363-3p treated animals. Our results support a therapeutic role for mir363-3p for long-term stroke disability.
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http://dx.doi.org/10.1016/j.bbi.2019.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488367PMC
May 2019

Sex differences in miRNA as therapies for ischemic stroke.

Neurochem Int 2019 07 2;127:56-63. Epub 2018 Nov 2.

Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, TX, 77807, USA.

MicroRNAs, a subset of non-coding RNAs, are present in virtually all tissues including body fluids and are global regulators of the transcriptome. In view of the expanding number of microRNAs and the large number of gene targets that each microRNA can potentially regulate, they have been compared to hormones in the scope of their effects. MicroRNA have been implicated as biomarkers for several diseases including stroke, as well as chronic conditions that are associated with stroke. Recent research has focused on manipulating miRNA to improve stroke outcomes. Although several miRNAs have been shown to have neuroprotective properties, the overwhelming majority of these studies have employed only male animals. This review will focus on two miRNAs, Let7f and mir363-3p, whose effectiveness as a stroke neuroprotectant is sex-specific.
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http://dx.doi.org/10.1016/j.neuint.2018.10.021DOI Listing
July 2019

Insulin-like Growth Factor (IGF)-1 treatment stabilizes the microvascular cytoskeleton under ischemic conditions.

Exp Neurol 2019 01 1;311:162-172. Epub 2018 Oct 1.

Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, TX 77807, United States. Electronic address:

Our previous studies showed that Insulin-like Growth Factor (IGF)-1 reduced blood brain barrier permeability and decreased infarct volume caused by middle cerebral artery occlusion (MCAo) in middle aged female rats. Similarly, cultures of primary brain microvessel endothelial cells from middle-aged female rats and exposed to stroke-like conditions (oxygen glucose deprivation; OGD) confirmed that IGF-1 reduced dye transfer across this cell monolayer. Surprisingly, IGF-1 did not attenuate endothelial cell death caused by OGD. To reconcile these findings, the present study tested the hypothesis that, at the earliest phase of ischemia, IGF-1 promotes barrier function by increasing anchorage and stabilizing cell geometry of surviving endothelial cells. Cultures of human brain microvessel endothelial cells were subject to oxygen-glucose deprivation (OGD) in the presence of IGF-1, IGF-1 + JB-1 (IGFR inhibitor) or vehicle. OGD disrupted the cell monolayer and reduced cell-cell interactions, which was preserved in IGF-1-treated cultures and reversed by concurrent treatment with JB-1. IGF-1-mediated preservation of the endothelial monolayer was reversed with LY294002 treatment, but not by Rapamycin, indicating that IGF-1 s actions on cell-cell contacts are likely mediated via the PI3K pathway. In vivo, microvessel morphology was evaluated in middle-aged female rats that were subjected to ischemia by MCAo, and treated ICV with IGFI, IGF-1 + JB-1, or artificial CSF (aCSF; vehicle) after reperfusion. Compared to vehicle controls, IGF-1 treated animals displayed larger microvessel diameters in the peri-infarct area and increased staining density for vinculin, an anchorage protein. Both these measures were reversed by concurrent IGF-1 + JB-1 treatment. Moreover these effects were restricted to 24 h after ischemia-reperfusion and no treatment effects were seen at 5d post stroke. Collectively, these data suggest that in the earliest hours during ischemia, IGF-1 promotes receptor-mediated anchorage of endothelial cells, and its actions may be accurately characterized as vasculoprotective.
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http://dx.doi.org/10.1016/j.expneurol.2018.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263796PMC
January 2019

Sex differences in the brain: Implications for behavioral and biomedical research.

Neurosci Biobehav Rev 2018 02;85:126-145

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States.

Biological differences between males and females are found at multiple levels. However, females have too often been under-represented in behavioral neuroscience research, which has stymied the study of potential sex differences in neurobiology and behavior. This review focuses on the study of sex differences in the neurobiology of social behavior, memory, emotions, and recovery from brain injury, with particular emphasis on the role of estrogens in regulating forebrain function. This work, presented by the authors at the 2016 meeting of the International Behavioral Neuroscience Society, emphasizes varying approaches from several mammalian species in which sex differences have not only been documented, but also become the focus of efforts to understand the mechanistic basis underlying them. This information may provide readers with useful experimental tools to successfully address recently introduced regulations by granting agencies that either require (e.g. the National Institutes of Health in the United States and the Canadian Institutes of Health Research in Canada) or recommend (e.g. Horizon 2020 in Europe) the inclusion of both sexes in biomedical research.
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http://dx.doi.org/10.1016/j.neubiorev.2017.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751942PMC
February 2018

Stroke triggers nigrostriatal plasticity and increases alcohol consumption in rats.

Sci Rep 2017 05 31;7(1):2501. Epub 2017 May 31.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, 77807, USA.

Excessive alcohol consumption is a known risk factor for stroke, but the effect of stroke on alcohol intake is unknown. The dorsomedial striatum (DMS) and midbrain areas of the nigrostriatal circuit are critically associated to stroke and alcohol addiction. Here we sought to explore the influence of stroke on alcohol consumption and to uncover the underlying nigrostriatal mechanism. Rats were trained to consume alcohol using a two-bottle choice or operant self-administration procedure. Retrograde beads were infused into the DMS or midbrain to label specific neuronal types, and ischemic stroke was induced in the dorsolateral striatum (DLS). Slice electrophysiology was employed to measure excitability and synaptic transmission in DMS and midbrain neurons. We found that ischemic stroke-induced DLS infarction produced significant increases in alcohol preference, operant self-administration, and relapse. These increases were accompanied by enhanced excitability of DMS and midbrain neurons. In addition, glutamatergic inputs onto DMS D1-neurons was potentiated, whereas GABAergic inputs onto DMS-projecting midbrain dopaminergic neurons was suppressed. Importantly, systemic inhibition of dopamine D1 receptors attenuated the stroke-induced increase in operant alcohol self-administration. Our results suggest that the stroke-induced DLS infarction evoked abnormal plasticity in nigrostriatal dopaminergic neurons and DMS D1-neurons, contributing to increased post-stroke alcohol-seeking and relapse.
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http://dx.doi.org/10.1038/s41598-017-02714-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451385PMC
May 2017

Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes.

Glia 2017 07 20;65(7):1043-1058. Epub 2017 Mar 20.

Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, Texas, 77807.

Middle aged female rats sustain larger stroke infarction and disability than younger female rats. This older group also shows age-related reduction of insulin like growth factor (IGF)-1 in serum and in astrocytes, a cell type necessary for poststroke recovery. To determine the impact of astrocytic IGF-1 for ischemic stroke, these studies tested the hypothesis that gene transfer of IGF-1 to astrocytes will improve stroke outcomes in middle aged female rats. Middle aged (10-12 month old), acyclic female rats were injected with recombinant adeno-associated virus serotype 5 (AAV5) packaged with the coding sequence of the human (h)IGF-1 gene downstream of an astrocyte-specific promoter glial fibrillary acidic protein (GFAP) (AAV5-GFP-hIGF-1) into the striatum and cortex. The AAV5-control consisted of an identical shuttle vector construct without the hIGF-1 gene (AAV5-GFAP-control). Six to eight weeks later, animals underwent transient (90 min) middle cerebral artery occlusion via intraluminal suture. While infarct volume was not altered, AAV5-GFAP-hIGF-1 treatment significantly improved blood pressure and neurological score in the early acute phase of stroke (2 days) and sensory-motor performance at both the early and late (5 days) acute phase of stroke. AAV5-GFAP-hIGF-1 treatment also reduced circulating serum levels of GFAP, a biomarker for blood brain barrier permeability. Flow cytometry analysis of immune cells in the brain at 24 hr poststroke showed that AAV5-GFAP-hIGF-1 altered the type of immune cells trafficked to the ischemic hemisphere, promoting an anti-inflammatory profile. Collectively, these studies show that targeted enhancement of IGF-1 in astrocytes of middle-aged females improves stroke-induced behavioral impairment and neuroinflammation.
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http://dx.doi.org/10.1002/glia.23142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432389PMC
July 2017

Fetal Alcohol Exposure Alters Blood Flow and Neurological Responses to Transient Cerebral Ischemia in Adult Mice.

Alcohol Clin Exp Res 2017 01 17;41(1):117-127. Epub 2016 Dec 17.

Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, Texas.

Background: Prenatal alcohol exposure (PAE) can result in physical and neurocognitive deficits that are collectively termed "fetal alcohol spectrum disorders" (FASD). Although FASD is associated with lifelong intellectual disability, the mechanisms mediating the emergence of secondary mental health and physical disabilities are poorly understood. Based on our previous data showing that maternal ethanol (EtOH) exposure in mice resulted in an immediate reduction in cranially directed fetal blood flow, we hypothesized that such exposure would also result in persistent alterations in cranially directed blood flow in the prenatally alcohol-exposed (PAE) adult. We also hypothesized that PAE adults exposed to an acute cerebrovascular insult would exhibit more brain damage and neurobehavioral impairment compared to non-PAE adult controls.

Methods: Pregnant C57BL/6 mice were exposed to EtOH, 3 g/kg, or water by intragastric gavage. Blood flow in carotid, renal, and femoral arteries was assessed by ultrasound imaging in PAE and control adults at 3, 6, and 12 months of age. To mimic ischemic stroke in young adult populations, 3-month-old PAE and control animals were subject to transient middle cerebral artery occlusion (MCAo) and subsequently assessed for behavioral recovery, stroke infarct volume, and brain cytokine profiles.

Results: PAE resulted in a significant age-related decrease in blood acceleration in adult mice, specifically in the carotid artery. A unilateral transient MCAo resulted in equivalent cortico-striatal damage in both PAE and control adults. However, PAE adult mice exhibited significantly decreased poststroke behavioral recovery compared to controls.

Conclusions: Our data collectively show that PAE adult mice exhibit a persistent, long-term loss of cranially directed blood flow, and decreased capacity to compensate for brain trauma due to acute-onset adult diseases like ischemic stroke.
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http://dx.doi.org/10.1111/acer.13277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501092PMC
January 2017

The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats.

J Neuroinflammation 2016 12 1;13(1):300. Epub 2016 Dec 1.

Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, College of Medicine, Texas A&M University Health Science Center, 8447 State Highway 47, Bryan, TX, 77807, USA.

Background: Sodium butyrate (NaB) is a histone deacetylase (HDAC) inhibitor exhibiting anti-inflammatory and neuroprotective effects in a rat ischemic model of stroke as well as a myocardial ischemia model. Although clinical evidence shows that older women are at higher risk for stroke occurrence and greater stroke severity, no studies have evaluated the effectiveness of NaB either in females or in older animals.

Methods: To determine the effects of NaB on stroke in older females, acyclic middle-aged Sprague-Dawley female rats (9-11 months old, constant diestrus) were subject to middle cerebral artery occlusion (MCAo) by intracerebral injection of recombinant endothelin-1. Rats were treated with NaB (300 mg/kg, i.p.) at 6 and 30 h following ET-1 injection. Animals were sacrificed at the early (2 days) or late (5 days) acute phase after MCAo. Serum and tissue lysates were collected for biochemical analyses.

Results: NaB treatment reduced infarct volume and ameliorated sensory motor impairment in middle-aged female rats, when measured at 2 and 5 days post MCAo. At the early acute phase (2 days post stroke), NaB treatment decreased brain lipid peroxides, and reduced serum levels of GFAP, a surrogate marker of blood-brain barrier (BBB) permeability. NaB also reduced expression of the inflammatory cytokine IL-1beta in circulation and IL-18 in the ischemic hemisphere. At the late acute phase (5 days post stroke), NaB treatment further suppressed MCAo-induced increase of IL-1beta, IL-17A, and IL-18 in brain lysates (cortex and striatum) from the ischemic hemisphere, and decreased ischemia-induced upregulation of IL-1beta and IL-18 in circulation, indicating a potent anti-inflammatory effect of the HDAC inhibitor. Moreover, NaB treatment also increased expression of IGF-1, a known neuroprotectant, in peripheral tissue including serum, liver, and spleen at the late acute phase.

Conclusions: These data provide the first evidence that delayed (>6 h) NaB treatment post-stroke is neuroprotective in older female rats. Additionally, these data also show that in addition to its well-known anti-inflammatory actions, NaB may exert a biphasic effect after stroke, operating initially to reduce BBB permeability and oxidative stress in the brain, and later, elevating IGF-1 expression in peripheral tissues.
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http://dx.doi.org/10.1186/s12974-016-0765-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131416PMC
December 2016

Sex differences in stroke therapies.

J Neurosci Res 2017 01;95(1-2):681-691

Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, Texas.

Stroke is the fifth leading cause of death and acquired disability in aged populations. Women are disproportionally affected by stroke, having a higher incidence and worse outcomes than men. Numerous preclinical studies have discovered novel therapies for the treatment of stroke, but almost all of these have been shown to be unsuccessful in clinical trials. Despite known sex differences in occurrence and severity of stroke, few preclinical or clinical therapeutics take into account possible sex differences in treatment. Reanalysis of data from studies of tissue plasminogen activator (tPA), the only currently FDA-approved stroke therapy, has shown that tPA improves stroke outcomes for both sexes and also shows sexual dimorphism by more robust improvement in stroke outcome in females. Experimental evidence supports the inclusion of sex as a variable in the study of a number of novel stroke drugs and therapies, including preclinical studies of anti-inflammatory drugs (minocycline), stimulators of cell survival (insulin-like growth factor-1), and inhibitors of cell death pathways (pharmacological inhibition of poly[ADP-ribose] polymerase-1, nitric oxide production, and caspase activation) as well as in current clinical trials of stem cell therapy and cortical stimulation. Overall, study design and analysis in clinical trials as well as in preclinical studies must include both sexes equally, consider possible sex differences in the analyses, and report the differences/similarities in more systematic/structured ways to allow promising therapies for both sexes and increase stroke recovery. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jnr.23855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125551PMC
January 2017

Sex differences in stroke: Review of current knowledge and evidence.

Vasc Med 2017 04 3;22(2):135-145. Epub 2016 Nov 3.

2 Baylor College of Medicine, Houston, TX, USA.

Stroke is a leading cause of death among women in the United States, and women are more affected by stroke than men. With women living longer than men, women experience not only a higher incidence of stroke but also more negative outcomes. Despite its lethal impact and high morbidity rate, the road from innovative bench research to improved clinical outcomes has been slow. This review explores the differential physiology, epidemiology, and clinical presentation of stroke between men and women, as well as the current status of laboratory and clinical data.
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http://dx.doi.org/10.1177/1358863X16668263DOI Listing
April 2017

Mir363-3p improves ischemic stroke outcomes in female but not male rats.

Neurochem Int 2017 Jul 20;107:168-181. Epub 2016 Oct 20.

Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan TX 77807, United States. Electronic address:

With age, stroke prevalence is higher, and stroke outcome, worse, in women. Thus there is an urgent need to identify stroke neuroprotectants for this population. Using a preclinical stroke model, our studies focused on microRNAs (miRNAs), a class of translational repressors, as neuroprotectants. Analysis of circulating miRNA in the acute phase of stroke indicated potential neuroprotective capacity for miR363. Specifically, mir363 is elevated in serum of adult female rats that typically have small infarct volumes, but is deficient in age-matched males or middle-aged males and females, groups that have greater stroke-associated impairment. To directly test the effect of mir363 on stroke outcomes, first, adult females were treated with antagomirs to mir363 post stroke and next, middle-aged females were treated with mimic to mir363-3p post stroke. Antagomir treatment to adult females significantly increased infarct volume and impaired sensory motor performance. Reciprocally, mir363 mimic to middle-aged females reduced infarct volume, preserved forebrain microvessels and improved sensory motor performance. In the early acute stroke phase, mir363-3p mimic reduced the expression and functional activity of caspase-3, a critical component of the apoptotic cell cascade. In contrast, mir363-3p mimic treatment had no effect on stroke outcomes or caspase regulation in young males. Collectively, these studies show that mir363 is neuroprotective for stroke in females and implicates caspase-3 as a sex-specific miRNA-sensitive node for recovery from ischemic stroke.
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http://dx.doi.org/10.1016/j.neuint.2016.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398946PMC
July 2017

Considering sex as a biological variable in preclinical research.

FASEB J 2017 01 28;31(1):29-34. Epub 2016 Sep 28.

Office of Research on Women's Health, National Institutes of Health, Bethesda, Maryland, USA.

In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT-OD-15-102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.-Miller, L. R., Marks, C., Becker, J. B., Hurn, P. D., Chen, W.-J., Woodruff, T., McCarthy, M. M., Sohrabji, F., Schiebinger, L., Wetherington, C. L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research.
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http://dx.doi.org/10.1096/fj.201600781RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191005PMC
January 2017

Prospects of modeling poststroke epileptogenesis.

J Neurosci Res 2017 04 25;95(4):1000-1016. Epub 2016 Jul 25.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas.

This Review describes the current status of poststroke epilepsy (PSE) with an emphasis on poststroke epileptogenesis modeling for testing new therapeutic agents. Stroke is a leading cause of epilepsy in an aging population. Late-onset "epileptic" seizures have been reported in up to 30% cases after stroke. Nevertheless, the overall prevalence of PSE is 2-4%. Rodent models of stroke have contributed to our understanding of the relationship between seizures and the underlying ischemic damage to neurons. To understand whether acutely generated stroke events lead to a chronic phenotype more closely resembling PSE with recurrent seizures, a limited variety of approaches emerged in early 2000s. These limited methods of causing an occlusion in mice and rats show different infarct size and neurological deficits. The most often employed procedure for inducing focal ischemia is the middle cerebral artery occlusion. This mimics the pathophysiology seen in humans in terms of extent of damage to cortex and striatum. Photothrombosis and endothelin-1 models can similarly evoke episodes of ischemic stroke. These models are well suited to studying mechanisms and biomarkers of epileptogenesis or optimizing novel drug discoveries. However, modeling of PSE is tedious, is highly variable, and lacks validity; therefore, it is not widely implemented in epilepsy research. Moreover, the relevance of ischemic models to specific forms of human stroke remains unclear. Stroke modeling in young male rodents lacks clinical relevance to elderly populations and especially to women, likely as a result of sex differences. Nevertheless, because of the neuronal damage and epileptogenic insult that these models trigger, they are helpful tools in studying acquired epilepsy and prophylactic drug therapy. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jnr.23836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266751PMC
April 2017

Sex Differences in the Impact of Shift Work Schedules on Pathological Outcomes in an Animal Model of Ischemic Stroke.

Endocrinology 2016 07 2;157(7):2836-43. Epub 2016 Jun 2.

Department of Neuroscience and Experimental Therapeutics (D.J.E., N.N., J.C., A.S., F.S.) and Women's Health in Neuroscience Program (A.S., F.S.), Texas A&M Health Science Center, College of Medicine, Bryan, Texas 77807-3260; and Department of Biology (D.J.E.) and Center for Biological Clocks Research (D.J.E.), Texas A&M University, College Station, Texas 77843-3258.

Circadian clock desynchronization has been implicated in the pathophysiology of cardiovascular disease and related risk factors (eg, obesity, diabetes). Thus, we examined the extent to which circadian desynchronization exacerbates ischemic stroke outcomes and whether its detrimental effects on stroke severity and functional impairments are further modified by biological sex. Circadian entrainment of activity rhythms in all male and female rats was observed during exposure to a fixed light-dark (LD) 12:12 cycle but was severely disrupted when this LD cycle was routinely shifted (12 h advance/5 d) for approximately 7 weeks. In contrast to the regular estrous cycles in fixed LD animals, cyclicity was abolished and persistent estrus was evident in all shifted LD females. The disruption of estrous cyclicity in shifted LD females was associated with a significant increase in serum estradiol levels relative to that observed in fixed LD controls. Circadian rhythm disruption exacerbated stroke outcomes in both shifted LD male and female rats and further amplified sex differences in stroke impairments. In males, but not females, circadian disruption after exposure to the shifted LD cycle was marked by high rates of mortality. In surviving females, circadian desynchronization after exposure to shifted LD cycles produced significant increases in stroke-induced infarct volume and sensorimotor deficits with corresponding decreases in serum IGF-1 levels. These results suggest that circadian rhythm disruption associated with shift work schedules or the irregular nature of our everyday work and/or social environments may interact with other nonmodifiable risk factors such as biological sex to modulate the pathological effects of stroke.
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http://dx.doi.org/10.1210/en.2016-1130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929545PMC
July 2016

Sex and the Lab: An Alcohol-Focused Commentary on the NIH Initiative to Balance Sex in Cell and Animal Studies.

Alcohol Clin Exp Res 2016 06 7;40(6):1182-91. Epub 2016 May 7.

Department of Neuroscience and Experimental Therapeutics , Texas A&M, Bryan, Texas.

In May 2014, Dr. Francis Collins, the director of U.S. National Institutes of Health (NIH), and Dr. Janine Clayton, the director of the U.S. National Institutes of Health Office of Research on Women's Health, published a commentary in the journal Nature announcing new policies to ensure that preclinical research funded by the NIH considers both males and females. While these policies are still developing, they have already generated great interest by the scientific community and triggered both criticism and applause. This review provides a description and interpretation of the NIH guidelines, and it traces the history that led to their implementation. As expected, this NIH initiative generated some anxiety in the scientific community. The use of female animals in the investigation of basic mechanisms is perceived to increase variability in the results, and the use of both sexes has been claimed to slow the pace of scientific discoveries and to increase the cost at a time characterized by declining research support. This review discusses issues related to the study of sex as a biological variable (SABV) in alcohol studies and provides examples of how researchers have successfully addressed some of them. A practical strategy is provided to include both sexes in biomedical research while maintaining control of the research direction. The inclusion of sex as an important biological variable in experimental design, analysis, and reporting of preclinical alcohol research is likely to lead to a better understanding of alcohol pharmacology and the development of alcohol use disorder, may promote drug discovery for new pharmacotherapies by increasing scientific rigor, and may provide clinical benefit to women's health. This review aims to promote the understanding of the NIH's SABV guidelines and to provide alcohol researchers with a theoretical and practical framework for working with both sexes in preclinical research.
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http://dx.doi.org/10.1111/acer.13072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889570PMC
June 2016

Why estrogens matter for behavior and brain health.

Neurosci Biobehav Rev 2017 05 31;76(Pt B):363-379. Epub 2016 Mar 31.

Department of Psychology and Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada.

The National Institutes of Health (NIH) has required the inclusion of women in clinical studies since 1993, which has enhanced our understanding of how biological sex affects certain medical conditions and allowed the development of sex-specific treatment protocols. However, NIH's policy did not previously apply to basic research, and the NIH recently introduced a new policy requiring all new grant applications to explicitly address sex as a biological variable. The policy itself is grounded in the results of numerous investigations in animals and humans illustrating the existence of sex differences in the brain and behavior, and the importance of sex hormones, particularly estrogens, in regulating physiology and behavior. Here, we review findings from our laboratories, and others, demonstrating how estrogens influence brain and behavior in adult females. Research from subjects throughout the adult lifespan on topics ranging from social behavior, learning and memory, to disease risk will be discussed to frame an understanding of why estrogens matter to behavioral neuroscience.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045786PMC
http://dx.doi.org/10.1016/j.neubiorev.2016.03.024DOI Listing
May 2017

Insulin-Like Growth Factor (IGF)-I Modulates Endothelial Blood-Brain Barrier Function in Ischemic Middle-Aged Female Rats.

Endocrinology 2016 Jan 10;157(1):61-9. Epub 2015 Nov 10.

Women's Health in Neuroscience Program (S.B., A.K.O., F.S.), Department of Neuroscience and Experimental Therapeutics and Department of Microbial Pathogenesis and Immunology (R.C.A.), Texas A&M University Health Science Center, Bryan, Texas 77807.

In comparison with young females, middle-aged female rats sustain greater cerebral infarction and worse functional recovery after stroke. These poorer stroke outcomes in middle-aged females are associated with an age-related reduction in IGF-I levels. Poststroke IGF-I treatment decreases infarct volume in older females and lowers the expression of cytokines in the ischemic hemisphere. IGF-I also reduces transfer of Evans blue dye to the brain, suggesting that this peptide may also promote blood-brain barrier function. To test the hypothesis that IGF-I may act at the blood-brain barrier in ischemic stroke, 2 approaches were used. In the first approach, middle-aged female rats were subjected to middle cerebral artery occlusion and treated with IGF-I after reperfusion. Mononuclear cells from the ischemic hemisphere were stained for CD4 or triple-labeled for CD4/CD25/FoxP3 and subjected to flow analyses. Both cohorts of cells were significantly reduced in IGF-I-treated animals compared with those in vehicle controls. Reduced trafficking of immune cells to the ischemic site suggests that blood-brain barrier integrity is better maintained in IGF-I-treated animals. The second approach directly tested the effect of IGF-I on barrier function of aging endothelial cells. Accordingly, brain microvascular endothelial cells from middle-aged female rats were cultured ex vivo and subjected to ischemic conditions (oxygen-glucose deprivation). IGF-I treatment significantly reduced the transfer of fluorescently labeled BSA across the endothelial monolayer as well as cellular internalization of fluorescein isothiocyanate-BSA compared with those in vehicle-treated cultures, Collectively, these data support the hypothesis that IGF-I improves blood-brain barrier function in middle-aged females.
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http://dx.doi.org/10.1210/en.2015-1840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701884PMC
January 2016

Astrocytic response to cerebral ischemia is influenced by sex differences and impaired by aging.

Neurobiol Dis 2016 Jan 2;85:245-253. Epub 2015 Apr 2.

Department of Neuroscience and Experimental Therapeutics, Texas A & M Health Science Center, College of Medicine, Bryan, TX 77807, USA. Electronic address:

Ischemic stroke occurs more often among the elderly, and within this demographic, women are at an increased risk for stroke and have poorer functional recovery than men. This is also well replicated in animal studies where aging females are shown to have more extensive brain tissue loss as compared to adult females. Astrocytes provide nutrients for neurons, regulate glutamate levels, and release neurotrophins and thus play a key role in the events that occur following ischemia. In addition, astrocytes express receptors for gonadal hormones and synthesize several neurosteroids suggesting that the sex differences in stroke outcome may be mediated through astrocytes. This review discusses key astrocytic responses to ischemia including, reactive gliosis, excitotoxicity, and neuroinflammation. In light of the age and sex differences in stroke outcomes, this review highlights how aging and gonadal hormones influence these responses. Lastly, astrocyte specific changes in gene expression and epigenetic modifications during aging and following ischemia are discussed as possible molecular mechanisms for impaired astrocytic functioning.
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http://dx.doi.org/10.1016/j.nbd.2015.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636213PMC
January 2016

Histone methylation patterns in astrocytes are influenced by age following ischemia.

Epigenetics 2015 3;10(2):142-52. Epub 2015 Feb 3.

a Women's Health in Neuroscience Program; Department of Neuroscience and Experimental Therapeutics; Texas A & M Health Science Center College of Medicine ; Bryan , TX USA ;

In animal models, middle-aged females sustain greater ischemia-induced infarction as compared to adult females. This age difference in infarct severity is associated with reduced functional capacity of astrocytes, a critical neural support cell. The impaired response of astrocytes following stroke in middle-aged females may be related to epigenetic alterations, including histone acetylation or methylation. The present study measured the activity of enzymes that regulate histone acetylation and methylation in cerebral cortical astrocytes of adult (6 month) and middle-aged (11+ month) female rats 48 h following middle cerebral artery occlusion. H3K4 histone methyltransferase activity was decreased in astrocytes from middle-aged females. The next experiment therefore examined H3K4me3 (transcriptional enhancer) and H3K9me3 (transcriptional repressor) in astrocytes from adult and middle-aged females using ChIP-seq analysis. Adult females had more enriched H3K4me3 peaks (304 vs. 26) at transcriptional start sites and fewer H3K9me3 enriched peaks than middle-aged females (4 vs. 22), indicating a pattern of less active chromatin in astrocytes in the older group following ischemia. DAVID clustering analysis of H3K4me3 enriched genes found several functional categories, including cell motility, regulation of apoptosis and the vascular endothelial growth factor (VEGF) pathway. H3K4me3 was enriched at the miR-17-20 cluster and VEGFa, and analysis of a separate set of astrocytes confirmed that VEGF protein expression and miR-20 mRNA expression were significantly greater following ischemia in adult females compared to middle-aged females. These data indicate that astrocytes display less active chromatin with aging and provide new insight into possible mechanisms for differences in stroke severity observed during aging.
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http://dx.doi.org/10.1080/15592294.2014.1001219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622874PMC
October 2015