Browsing by Subject "stroke"
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Item A Novel Prodrug Approach for Central Nervous System-Selective Estrogen Therapy(MDPI, 2019-11-19) Prokai-Tatrai, Katalin; Prokai, LaszloBeneficial effects of estrogens in the central nervous system (CNS) results from the synergistic combination of their well-orchestrated genomic and non-genomic actions, making them potential broad-spectrum neurotherapeutic agents. However, owing to unwanted peripheral hormonal burdens by any currently known non-invasive drug administrations, the development of estrogens as safe pharmacotherapeutic modalities cannot be realized until they are confined specifically and selectively to the site of action. We have developed small-molecule bioprecursor prodrugs carrying the para-quinol scaffold on the steroidal A-ring that are preferentially metabolized in the CNS to the corresponding estrogens. Here, we give an overview of our discovery of these prodrugs. Selected examples are shown to illustrate that, independently of the route of administrations and duration of treatments, these agents produce high concentration of estrogens only in the CNS without peripheral hormonal liability. 10beta,17beta-Dihydroxyestra-1,4-dien-3-one (DHED) has been the best-studied representative of this novel type of prodrugs for brain and retina health. Specific applications in preclinical animal models of centrally-regulated and estrogen-responsive human diseases, including neurodegeneration, menopausal symptoms, cognitive decline and depression, are discussed to demonstrate the translational potential of our prodrug approach for CNS-selective and gender-independent estrogen therapy with inherent therapeutic safety.Item Chronic testosterone deprivation sensitizes the middle-aged rat brain to damaging effects of testosterone(2020-05) Smith, Charity; Schreihofer, Derek A.; Cunningham, Rebecca L.; Singh, Meharvan; Yang, Shaohua; Jones, Harlan P.Levels of the testosterone (T) fall in aging men. Recently, the number of men obtaining testosterone replacement therapy (TRT) has increased dramatically. However, other consequences of aging, such as increased oxidative stress, may result in detrimental effects when combined with TRT, including an increased stroke risk. Whether such a delay would alter the effects of TRT on stroke is not known. We hypothesized that a delay TRT following castration in middle-aged male rats would result in increased oxidative stress and a reduction in the neuroprotective effects of testosterone following stroke. We evaluated the effects of testosterone treatment after short (2 week) and long-term testosterone deprivation (10 weeks) in middle-aged male rats on cerebral ischemia, oxidative stress and cognitive function. Our data suggest testosterone treatment after long-term hypogonadism can exacerbate functional recovery after focal cerebral ischemia, however in the absence of injury improves cognition. Both effects are regulated by oxidative stress.Item DIETARY SUPPLEMENTS INFLUENCE ACTIVITY OF ACID-SENSING ION CHANNELS(2014-03) Agharkar, Amruta S.; Gonzales, Eric B.Dietary supplements or nutraceutical industry contributes billions of dollars to Unites States economy every year. The dietary supplement we intend to study is one of the most commonly used nutraceutical available in the market over the counter. It is used primarily by athletes and body builders to build lean body mass. Studies have shown that DS is effective in neuroprotection after stroke and also helps in improving muscle strength in patients suffering from muscle weakness or osteoarthritis. We are studying the effect of DS on acid-sensing ion channels (ASICs) which are the major contributors to neuronal damage after ischemia and pain. Determining the activity of DS on ASICs will give the new preventive measure for stroke and pain. Purpose (a): Dietary supplements and nutraceuticals have been the focus of research to identify novel therapeutics for a variety of pathologies, including the prevention of long-term consequences of stroke and reducing pain. Ion channels offer a growing group of molecular targets for treatment, which include the acid-sensing ion channels (ASICs). Acid-sensing ion channels (ASICs) are sodium channels that are sensitive to changes in extracellular pH, specifically those changes following injury and ischemia. These channels are expressed most prominently in peripheral and central nervous system. Their role in physiology is yet to be fully understood, but these channels have been implicated in pain sensation and centrally in the neurodegeneration following ischemic stroke. We identified an over-the-counter dietary supplement (DS) that shares similarity to guanidine compounds that selectively modulate acid-sensing ion channels. Thus, we hypothesize that this dietary supplement inhibits channel activity in acid-sensing ion channels. Methods (b): We will utilize whole cell patch-clamp electrophysiology technique to determine the intrinsic activity of DS on ASICs. The current elicited in absence and presence of DS at various pH will be normalized to maximum peak current obtained with control. Results (c): Our preliminary data show that DS decreased the ASIC1a pH sensitivity by shifting the observed proton activation profile to the right. Furthermore, we observed a change in the Hill coefficient of the DS influenced ASIC1a steady-state desensitization profile. Conclusions (d): Based on our preliminary data, we can conclude that DS influences ASIC current amplitude and steady state desensitization profile. Future experiments will focus on determining the influence of DS on other acid-sensing ion channel subtypes and identifying the DS binding site with the protein structure.Item Estrogen administration attenuates post-stroke depression by enhancing CREB/BDNF/TrkB signaling in the rat hippocampus(Spandidos Publications, 2021-02-26) Jiang, Huigang; Xiao, Li; Jin, Kunlin; Shao, BeiA previous study demonstrated that 17beta-estradiol (E2), which is an antidepressant, can ameliorate post-stroke depression (PSD); however, the underlying mechanisms governing this remain largely unknown. Therefore, the present study developed a PSD model in rats, which was induced by left middle cerebral artery occlusion followed by exposure to chronic mild stress for 2 weeks. The results revealed that the activity of the cAMP response element-binding protein (CREB), a cellular transcription factor, and the associated brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling were all attenuated in the hippocampus in PSD rats. The depression-like behaviors were significantly improved after treatment with E2, along with increased CREB and the BDNF/TrkB signaling activity. These results provide novel insight into the molecular basis of PSD, and suggest the potential involvement of CREB/BDNF/TrkB signaling in E2-mediated improvement of PSD in rats.Item INHIBITION OF HYPOXIA INDUCIBLE FACTOR 1A BY SOY PHYTOESTROGENS: A POTENTIAL MECHANISM FOR NEUROPROTECTION IN STROKE(2013-04-12) Namuduri, AnuradhaPurpose: Despite a multitude of endogenous mechanisms to compensate for transient decreases in glucose and oxygen delivery to the brain, ischemic stroke remains the third leading cause of death and the leading cause of long-term disability in the United States. Studies in animal models of cerebral ischemia have shown that both endogenous and exogenous estrogens improve histological and behavioral stroke outcomes. Similarly, phytoestrogens derived from soy and other plant products can reduce stroke injury in the lab. These compounds are structurally similar to estrogen and bind to and activate estrogen receptors. Our overall hypothesis is that soy phytoestrogens can induce adaptive responses in the brain to favor increased survival and cell repair. One early adaptive response to ischemia is activation of the oxygen homeostasis mediator hypoxia-inducible factor 1 alpha (HIF-1 alpha), a normally labile protein that is stable under conditions of low oxygen. Despite the importance of HIF-1 alpha in the adaptive response to hypoxia and ischemia, acute overactivation of this protein increases cerebral edema and cell death. The purpose of this research is to determine if soy phytoestrogens (genistein, daidzein, equol) inhibit acute ischemic injury by attenuating the detrimental actions of HIF-1 alpha. Methods: In vitro, HT22 hippocampal cells were treated with 0.1 or 1 micromolar genistein and exposed to oxygen and glucose deprivation to mimic conditions of ischemia within the brain. In vivo, ovariectomized female Sprague Dawley rats were fed a soy-free or high soy diet for 4 weeks followed by 90 minutes experimental stroke and 4-24 hours of recovery. HIF-1 alpha levels were determined by Western blotting for the HIF-1 alpha targets vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and BCL2/adenovirus E1B 19kDa interacting protein 3 (BNIP3). Results: In HT22 cells, genistein attenuated the HIF-1 alpha response to ischemia and increased degradation of HIF-1 alpha. Rats fed a high soy diet had significantly decreased levels of HIF-1 alpha and it's targets VEGF, eNOS, and BNIP3 in the ischemic hemisphere compared to rats on a soy-free diet. Conclusions: These results suggest that one mechanism of phytoestrogen neuroprotection is the attenuation of acute detrimental effects of HIF-1 alpha. These results further support the potential for dietary phytoestrogens as an effective prophylactic step in the prevention and management of ischemic strokes.Item INHIBITION OF LET-7I AS A MEANS TO ENHANCE THE NEUROPROTECTIVE EFFICACY OF PROGESTERONE IN THE ISCHEMIC BRAIN(2018-05) Nguyen, Trinh V.; Singh, Meharvan; Basu, Alakananda; Ghorpade, Anuja; Cunningham, Rebecca L.; Yang, ShaohuaThe occurrence of ischemic stroke is relatively rare among pre-menopausal women. Strikingly, this risk doubles every 10 years after the menopausal transition; and women are likely to experience worse outcomes and higher mortality post stroke than men. Since both estrogen (E2) and progesterone (P4) levels decline precipitously following the menopause, this hormonal reduction may, at least partially, contribute to the higher risk and worse outcomes. By inference, these hormones could play a critical role in protecting women against ischemic stroke. In this dissertation project, we focus on P4, the relatively understudied of the two hormones. And while P4 has been shown to be a potent neuroprotectant in various experimental models of stroke, the underlying mechanisms remain unclear. One known mediator of P4's protective function is brain-derived-neurotrophic-factor (BDNF), which has an established role in promoting neuronal differentiation, survival, and synaptogenesis. In addition, emerging literature and data from our laboratory strongly support the indispensable role of glia in P4's neuroprotective program and thus, may also play a significant role in post-stroke recovery. We recently reported that P4 induces a significant release of BDNF from primary astrocytes, through a putative membrane-associated progesterone receptor consisting of progesterone-receptor-membrane-component-1 (Pgrmc1). This receptor is abundantly expressed in various regions of brain and mediates such effects of P4 in the central nervous system (CNS) as anti-apoptotic effects, spinogenesis, and BDNF release. What is not known, however, is how the expression of this receptor is regulated. This dissertation was aimed to elucidate what regulates the expression of Pgrmc1 and BDNF in glia and how such regulation influences the neuroprotective function of P4 in the ischemic brain. Based on the observation that Let-7i regulates the expression of Pgrmc1 in a peripheral cell type, and our in silico analysis that revealed that both Pgrmc1 and BDNF are potential targets of let-7i, we hypothesized that let-7i represses P4's neuroprotective effects by down-regulating the expression of both Pgrmc1 and BDNF in glia, leading to: 1) suppression of P4-induced BDNF release from glia, and 2) attenuation of the beneficial effects of P4 on neuronal survival and markers of synaptogenesis in the ischemic brain. Using primary cortical astrocytes as an experimental model, we found that let-7i negatively regulated the expression of Pgrmc1 and BDNF. This was correlated with a reduction in P4-induced BDNF release from these cells. Under such conditions of reduced expression of both Pgrmc1 and BDNF, P4 was unable to protect primary neurons against oxygen-glucose-deprivation (OGD) or regulate markers of synaptogenesis. In our in vivo model of transient ischemic stroke, we found that protective effects of P4 were greatly enhanced in animals that were concomitantly treated with an inhibitor (antagomir) of let-7i. The combined treatment also enhanced synaptogenesis in the peri-infarct region. Collectively, the data presented here suggested that in the ischemic brain, let-7i negatively influences P4-induced neuroprotection via regulation of the Pgrmc1/BDNF axis. As such, inhibition of let-7i maybe an effective means to enhance the efficacy of P4 in treating ischemic stroke.Item Intensity of Usual Care Therapeutic Interventions in Inpatient Rehabilitation - A Pilot Study(2019-12) Di Pasquale, Jake A.; Millar, J. Cameron; Ranjan, Amalendu P.Minimal evidence exists describing key dosing parameters of interventions used during the subacute phase of recovery after neurological injury. This prospective cohort study aims to assess cardiorespiratory strain resulting from novel and conventional therapeutic interventions. Gait training provided relatively more moderate to vigorous exercise, reaching the associated %HRR 25% and 42% of the time in patients post spinal cord injury (SCI) and stroke, respectively. Specifically, EksoGT overground robotic gait training appears more effective, evoking targeted %HRR for 48% and 52% of sessions. Rate of Perceived Exertion (RPE) was moderately correlated with very light intensity in patients with SCI but ultimately ineffective at gauging %HRR. EksoGT can administer moderate to vigorous intensity exercise to patients with severe disabilities. Inpatient rehabilitation is inherently variable in method and population but can provide minimally sufficient exercise intensity. Further research into the dose-response relationship and accurate estimation of intensity are needed.Item MITOCHONDRIAL ENCEPHALOMYOPATHY, LACTIC ACIDOSIS, AND STROKE-LIKE SYNDROME: A CASE REPORT(2013-04-12) Quackenbush, DavidPurpose: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), is a rare syndrome inherited through mitochondrial DNA, and thus from the female parent. This case study serves to educate health professionals in the diagnosis, care, and prognosis of individuals with MELAS syndrome. Methods: Information for this case report was collected retrospectively from electronic medical records of the patient's clinical encounters at a family medicine clinic. This information was compared to other case reports and research done on MELAS syndrome and compiled for a poster presentation. Results: MELAS syndrome is a multisystem illness, and individuals often have varied presentations. MELAS syndrome is often found during childhood, and there are several key symptoms that should raise a clinician's suspicion. The patient presented in the case report had many of the health issues associated with MELAS syndrome including seizures and a stroke at a young age. Conclusions: This case report demonstrates the effect MELAS syndrome has on an individual. The case serves to educate health professionals in the common presentation of this rare mitochondrial disease and discusses different treatment modalities that have been attempted among other affected individuals.Item Obesity and Risk of Stroke in NHANES I Follow Up Study(2002-12-01) Soman, Ashwini; Ajani, Umed; Rene, Antonio; Singh, KaranSoman, Ashwini, Obesity and risk of stroke in NHANES-I follow-up study, Masters of Public Health (Epidemiology), December 2002. 79pp., 20 tables, 3 illustrations, bibliography, 46 titles. Stroke is the third leading cause of death in the US. Role of obesity as an independent risk factor has been relatively well established for coronary heart diseases but not for stroke. Purpose of this study was to assess long-term risk of stroke due to obesity measured at baseline. The research was conducted using First National Nutritional Health and Examination Survey and its follow ups. Overall, increased risk of stroke was observed in obese individuals (BMI [greater than] 30 kg/m2). Similar association was observed in different subgroups of race, gender, those with or without diabetes and cardiovascular disease.Item Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases(JKL International, 2017-07-21) Xu, Xianglai; Wang, Brian; Ren, Changhong; Hu, Jiangnan; Greenberg, David A.; Chen, Tianxiang; Xie, Liping; Jin, KunlinAs with many age-related diseases including vascular dysfunction, age is considered an independent and crucial risk factor. Complicated alterations of structure and function in the vasculature are linked with aging hence, understanding the underlying mechanisms of age-induced vascular pathophysiological changes holds possibilities for developing clinical diagnostic methods and new therapeutic strategies. Here, we discuss the underlying molecular mediators that could be involved in vascular aging, e.g., the renin-angiotensin system and pro-inflammatory factors, metalloproteinases, calpain-1, monocyte chemoattractant protein-1 (MCP-1) and TGFbeta-1 as well as the potential roles of testosterone and estrogen. We then relate all of these to clinical manifestations such as vascular dementia and stroke in addition to reviewing the existing clinical measurements and potential interventions for age-related vascular dysfunction.Item Risk for Stroke Among Migraine Sufferers(2001-05-01) Hall, Rebecca G.; Rene, Antonio; Bayona, ManuelHall, Rebecca G., Risk for Stroke Among Migraine Sufferers. Master of Public Health (Epidemiology), May, 2000, 27 pp., 9 tables, references, 33 titles. The objective of this study was to investigate, using the National Health Interview Survey (NHIS), whether those who suffer from migraine or severe headache do. Odds ratios were calculated for stroke among migraine sufferers compared to those who do not suffer from migraine. Results were adjusted for age, gender, and race. Risk factors for stroke were also analyzed. The crude odds ratio for stroke among migraine sufferers compared to non-migraine sufferers is 2.17, increasing 3.77 with age-adjustment. These results suggest that vascular events that are associated with migraine may also be associated with an increased risk for stroke. Discovering the mechanism that generates this relationship has widespread implication to the population and may save taxpayers billions of dollars annually be leading to better treatments for and possible prevention of migraine.Item SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke(JKL International, 2018-04-01) Zhang, Yu; Zhang, Hongxia; Lin, Siyang; Chen, Xudong; Yao, Yu; Mao, XiaoOu; Shao, Bei; Zhuge, Qichuan; Jin, KunlinStromal-derived factor-1 (SDF-1, also known as CXCL12) and its receptors CXCR4 and CXCR7 play important roles in brain repair after ischemic stroke, as SDF-1/ CXCR4/CXCR7 chemokine signaling is critical for recruiting stem cells to sites of ischemic injury. Upregulation of SDF-1/CXCR4/CXCR7 chemokine signaling in the ischemic regions has been well-documented in the animal models of ischemic stroke, but not in human ischemic brain. Here, we found that protein expression of SDF-1 and CXCR7, but not CXCR4, were significantly increased in the cortical peri-infarct regions (penumbra) after ischemic stroke in human, compared with adjacent normal tissues and control subjects. Double-label fluorescence immunohistochemistry shows that SDF-1 and CXCR4 proteins were expressed in neuronal cells and astrocytes in the normal brain tissue and peri-infarct regions. CXCR7 protein was also observed in neuronal cells and astrocytes in the normal cortical regions, but predominantly in astrocytes in the penumbra of ischemic brain. Our data suggest that ischemic stroke in human leads to an increase in the expression of SDF-1 and CXCR7, but not CXCR4, in the peri-infarct cerebral cortex. Our findings suggest that chemokine SFD-1 is expressed not only in animal models of stroke, but also in the human brain after an ischemic injury. In addition, unlike animals, CXCR7 may be the primary receptor of SDF-1 in human stroke brain.Item TRANSIENT FOCAL CEREBRAL ISCHEMIA INDUCED LONG-TERM COGNITIVE FUNCTION DEFICIT IN AN EXPERIMENTAL ISCHEMIC STROKE MODEL(2013-04-12) Li, WenjunPurpose: Vascular dementia incorporates cognitive dysfunction with vascular disease, which ranks as the second leading cause of dementia in the United States. However, its underlying pathophysiological mechanism is not fully understood and no effective treatment is available. The purpose of the current study was to evaluate long-term cognitive deficits induced by transient middle cerebral artery occlusion (MCAO) in rats and to investigate the potential underlying mechanism. Methods: Sprague-Dawley rats were subjected to transient MCAO or sham surgery. Behavior tests for locomotor activity and cognitive function were conducted at 7 or 30 days after stroke. Hippocampal long term potentiation (LTP) and involvement of GABAergic signaling were evaluated at 30 days after sham surgery or stroke. Immunohistochemistry and Western blots analysis were conducted to determine the effect of MCAO on cell signaling at the hippocampus. Results: Transient MCAO induced progressive decline of cognitive function. At 30 days after stroke, no neuron loss or synaptic makers change in the hippocampus was observed. Reduction of LTP in both side hippocampus was observed at 30 days after stroke, which could be attenuated by blocking of GABAergic signaling. ERK activation was significantly reduced in both side hippocampus at 30 days after stroke. Conclusions: The present study identified a progressive decline of cognitive function after transient focal cerebral ischemia that correlated with suppression of hippocampal LTP, elevation of GABAergic signaling, and inhibition of ERK activation. Our study indicated that attenuating GABAergic activity or enhancing ERK/MAPK activation in the hippocampus might be potential therapeutic targets to prevent and attenuate cognitive function impairment after ischemic stroke.