Browsing by Subject "cognition"
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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 Antioxidants, Exercise, APOE Genotype and Brain Function(2014-12-01) Chaudhari, Kiran; Nathalie Sumien; Michael J. Forster; Eric B. GonzalesApolipoprotein E4 (APOE4) is a well-established and extensively prevalent genetic risk factor for the development of Alzheimer’s disease (AD). The presence of APOE4 allele accelerates the pathophysiology and symptomology of AD. A large set (36%) of the population suffering from AD expresses APOE4. Being a chronic progressive disease with very few pharmaco-therapeutic agents approved by FDA, non-drug lifestyle modifications have been an important part of management of AD. People often eat healthy diet rich in antioxidants and focus on healthy living habits such as exercise. Health care providers frequently suggest combining antioxidants with physical activity for higher benefits. Antioxidants have been beneficial in counteracting oxidative stress and improving learning and memory. Similarly, different regimens of exercise also improved cognition and delayed development of AD. However, the nature of the interaction between antioxidants and exercise remain elusive and complicated. While some studies reported additive effects, others have also shown a concerning antagonistic action of the antioxidants on the beneficial effects of exercise. In the context of APOE genotype, we set our study to determine the nature of such interaction between antioxidants and exercise. Using vitamins C and E and a treadmill-based forced exercise in a genetically modified mouse model expressing human APOE3 and APOE4 (GFAP-APOE3, GFAP-APOE4), we explored the nature of that interaction on functional and biochemical outcomes. We examined the mice for spatial learning and memory, working memory and executive function, coordinated running performance, muscular reflexes, spontaneous locomotor activity, anxiety and muscle strength. Interestingly, we observed that the young adult mice expressing E4 allele performed better on higher brain functions including spatial learning and memory and short term memory in contrast to middle age mice, which developed a cognitive deficit as expected. Motor functions, reflexes and coordination were poor among all the mice carrying E4 allele irrespective of age. Antioxidants and exercise interventions led to outcomes that were dependent on genotype, age and the brain function under consideration. There was additive beneficial effect of combination of antioxidants and exercise on cognitive outcomes but not on motor outcomes in middle age groups. However, in young adults, an antagonistic interaction was observed on motor outcomes but no such interaction was observed on cognitive outcomes. Hence we can conclude that, combination of antioxidants and exercise is not a “fit for all” approach and needs to be tailored base on individual’s age and genotype.Item ApoE Genotype-Dependent Response to Antioxidant and Exercise Interventions on Brain Function(MDPI, 2020-06-25) Chaudhari, Kiran; Wong, Jessica M.; Vann, Philip H.; Como, Tori; O'Bryant, Sid E.; Sumien, NathalieThis study determined whether antioxidant supplementation is a viable complement to exercise regimens in improving cognitive and motor performance in a mouse model of Alzheimer's disease risk. Starting at 12 months of age, separate groups of male and female mice expressing human Apolipoprotein E3 (GFAP-ApoE3) or E4 (GFAP-ApoE4) were fed either a control diet or a diet supplemented with vitamins E and C. The mice were further separated into a sedentary group or a group that followed a daily exercise regimen. After 8 weeks on the treatments, the mice were administered a battery of functional tests including tests to measure reflex and motor, cognitive, and affective function while remaining on their treatment. Subsequently, plasma inflammatory markers and catalase activity in brain regions were measured. Overall, the GFAP-ApoE4 mice exhibited poorer motor function and spatial learning and memory. The treatments improved balance, learning, and cognitive flexibility in the GFAP-ApoE3 mice and overall the GFAP-ApoE4 mice were not responsive. The addition of antioxidants to supplement a training regimen only provided further benefits to the active avoidance task, and there was no antagonistic interaction between the two interventions. These outcomes are indicative that there is a window of opportunity for treatment and that genotype plays an important role in response to interventions.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 CURCUMIN SUPPLEMENTATION IMPROVES CERTAIN ASPECTS OF COGNITION AND ALLEVIATES INFLAMMATION, INDEPENDENT OF ADIPOSITY(2014-03) Sarker, Marjana R.; Franks, Susan F.; Sumien, Nathalie; Filipetto, Frank; Forster, MichaelThe study was designed to investigate the effects of curcumin on blood based biomarkers and mental health in a chronic mid-life obese state. 3 groups were studied, mice on a regular diet, on a calorically restricted diet and on a regular diet supplemented with curcumin. These mice were kept on their respective diets for 12 weeks. Two behavioral studies to investigate mental health in particular memory, were utilized. Our results conclude that curcumin dietary treatment positively affects specific domains of mental health possibly by the lowering of inflammation but this effect is independent of fat loss. Purpose (a): Midlife obesity has been recently associated with cognitive impairment that may be attributed to chronic, obesity-related inflammation and oxidative stress. Commonly used laboratory mice fed ad libitum are an analogue of weight gain in middle aged humans, since accumulating fat is more often the result of food intake exceeding energy expenditure and not solely because of a high fat diet. The current study addressed the hypothesis that curcumin supplementation, by attenuating obesity and adiposity -related inflammation, would improve cognition in a midlife obesity animal model. Methods (b): C57BL/6J male mice were maintained under ad libitum (AL) feeding until they reached peak weight at 15 months of age, as a model of inactivity-related weight gain. The mice were subsequently assigned in groups of 19 to: (i) remain on AL, (ii) receive 30% caloric restriction (CR) or (iii) receive curcumin in their AL diet (1000 mg/kg diet, CURC) for 12 weeks. Mice underwent tail bleeds for the inflammatory markers, interleukin 6 (IL-6) and C-reactive protein (CRP) and, after 8 weeks of dietary treatment, spatial cognitive function was tested using a Morris water maze, followed by testing for cognitive flexibility using a discriminated avoidance, serial reversal task. Visceral (VAT) and subcutaneous (SAT) adipose tissue was collected after 12 weeks of the treatments. Results (c): Mice maintained on CR weighed significantly less than mice on the CURC and AL diets by the third week of treatment. Food intake of the CURC group was significantly higher than AL. Mice on CR and CURC diets took fewer trials than AL to reach criterion during the second reversal session of discriminated avoidance, suggesting that both conditions improved cognitive flexibility. However, there were no significant differences between the groups in their spatial cognitive performance. Mice maintained on CR had significantly less VAT and SAT compared to mice on CURC and AL. Curcumin supplementation did not significantly impact IL-6 levels but it did reduce CRP relative to AL mice. Conclusions (d): Results suggest that in a midlife obesity animal model, curcumin supplementation has positive effects on frontal cortical functions that may be linked to an anti-inflammatory action. It appears that these effects may be independent of adiposity. Curcumin intake may also facilitate energy expenditure or diminish efficiency, as suggested by the increase in energy intake in the absence of weight loss in the CURC mice. Future studies will determine the metabolic and cognitive consequences of higher curcumin doses.Item Dietary Curcumin And Caloric Restriction As Interventions For The Reversal Of Age Associated Functional Decline(2015-12-01) Sarker, Marjana R.; Forster, Michael J.; Franks, Susan; Sumien, NathalieAugmentation and exacerbation of oxidative stress and low-grade chronic systemic inflammation during mid-life has been proposed as modifiable causative factors for neurobehavioral decline reported with normal aging. Physiologically, the imbalance of pro-oxidants and endogenous antioxidants leads to an increase in tissue- damaging oxidative stress. Aging has also been associated with chronic systemic inflammation that can damage healthy tissues and diminish cognitive and motor capacity. The overall hypothesis of this project is that caloric restriction and dietary curcumin, via their strong anti-oxidant and anti-inflammatory properties; can delay the onset or ameliorate cognitive and motor decline in middle aged and aged mice respectively. Study 1: Fifteen month-old male C57BL/6 mice were tested as a model of sedentary mid-life obesity for the pilot study. They underwent dietary treatment for 12 weeks and were subjected to cognitive tests at the 8th week of treatment. Dietary treatments included regular chow fed ad libitum (AL), curcumin (1g/kg of diet) fed ad libitum (CURAL) and 30% to weight stable caloric restriction (CR). Mice were tested for spatial learning and cognitive flexibility testing. Blood was collected to measure inflammation and oxidative stress. Results from the pilot study indicated a significant weight loss and reduced adiposity in the CR group; whereas CURAL mice maintained stable weight throughout the treatment, consumed more food than the AL mice, and did not show a reduction of adipose tissue. However, both the CR and CURAL groups took fewer trials than AL to reach criterion during the reversal sessions of the active avoidance task, suggesting an improvement in cognitive flexibility. The AL mice had higher levels of CRP compared to CURAL and CR, and reduced glutathione as well as the GSH/GSSG ratio were increased during curcumin intake, suggesting a reducing shift in the redox state. Study 2: In the subsequent study, 15 and 20 month old female and male C57BL/6 mice were used as a normal aging model to study functional decline. This study included all of the dietary interventions from the pilot study and an additional combination diet of CR and curcumin (CURCR). Curcumin was added to the diet at 7g/kg of diet with mice under CURCR receiving 7.2g/kg of diet, adjusted to take difference in food intake into account. The mice underwent dietary treatments for 4 months, and cognitive and motor behavior tests were conducted at 8 weeks of treatment. Mice were tested on multiple tasks that are sensitive to age associated cognitive and motor dysfunction. Results from the second study indicated females to be more active than males. Mice under CR and CURCR performed better in the motor tests compared to their age matched controls, which included coordinated running, wire suspension and bridge walking. Cognitive flexibility was significantly better for middle-aged males under CR and CURAL compared to AL but not under CURCR, suggesting an antagonistic interaction. On the other hand, middle aged and aged female experimental groups did significantly better than AL. No interaction of CR and CUR was observed in aged males, with CURAL and CR yielding comparable benefits. None of the treatments had a significant effect on hippocampus- dependent rate of learning in middle age or the aged; however middle aged males under the CURCR intervention had poorer probe performance compared to their age matched controls. Data from both projects suggest that independent of weight loss; dietary curcumin and CR have positive effects on fronto-cortical functions in late middle age and senescence that could be linked to anti-inflammatory or antioxidant actions. These effects were similar across different behavioral tasks and were non-additive or antagonistic in a sex dependent manner, suggesting that they could involve the same or similar mechanisms including an influence of sex hormones. Therefore, curcumin intake may mimic the neurobehavioral outcomes of CR that could be age dependent, but the mechanism of action underlying the outcomes of the CR and curcumin combination treatments need to be further examined.Item MRI biomarkers of small vessel disease and cognition: A cross-sectional study of a cognitively normal Mexican American cohort(Wiley Periodicals, LLC, 2021-10-14) Vintimilla, Raul; Hall, James R.; King, Kevin; Braskie, Meredith N.; Johnson, Leigh A.; Yaffe, Kristine; Toga, Arthur W.; O'Bryant, Sid E.Background: The current project sought to evaluate the impact that white matter hyperintensities (WMH) have on executive function in cognitively normal Mexican Americans, an underserved population with onset and more rapid progression of dementia. Methods: Data from 515 participants (360 female) enrolled in the Health and Aging Brain Study: Health Disparities project were analyzed. Participants underwent clinical evaluation, cognitive testing, and a brain MRI. Linear regression was used to predict the effect of total WMH volume on cognitive test scores. Age, sex, and education were entered as covariates. Results: Regression analysis showed that WMH volume significantly predicted executive function. WMH also predicted global cognition and attention scores, although not significantly after adjusting for age. Conclusion: In this sample of cognitively normal Mexican Americans, we found that WMH volume was associated with lower scores in a measure of executive function, after accounting for age, sex, and education.Item Neurobehavioral and biochemical consequences of chronic, low-dose methamphetamine exposure in male and female mice(2022-08) Davis, Delaney L.; Sumien, Nathalie; Huang, Ren-Qi; Gatch, Michael B.; Phillips, Nicole R.; Schreihofer, Derek A.; Ma, RongAlthough prescription psychostimulants are effective in reducing attention deficit hyperactivity disorder (ADHD) symptomology, misuse of these drugs can pose serious risks such as potential abuse, dependence, and/or neurotoxicity. Of particular concern is that young adults have the highest prevalence of prescription stimulant misuse, with almost 10% of college students admitting to using amphetamine (e.g. Adderall) or methylphenidate (e.g. Ritalin) products. Despite these drugs being widely used for therapeutic and recreational use, the long-term effects of prescription stimulants have not been systematically evaluated in controlled clinical trials. Therefore, it is critical to conduct this research because young adults may be a vulnerable, at-risk population to the potential adverse consequences of long-term amphetamine use. This dissertation research evaluates the biochemical and behavioral consequences of chronic exposure of the prototypical psychostimulant, methamphetamine (METH), in a rodent model. It is hypothesized that repeated doses of METH, within the therapeutic dosing range used in a clinical setting, will induce neurotoxicity through the interplay of biological mechanisms of oxidative stress, glutamate excitotoxicity, neuroinflammation and epigenetic alterations and increase susceptibility to addiction that will be exacerbated by aging processes. Overall, the body of results showed short-term alterations in brain biochemistry and behavioral function, that do not necessarily persist past 5 months after METH treatment. In conclusion, this dissertation highlights the importance of long-term studies in addressing prescription stimulant misuse in an adult population to better understand the safety of these widely used and prescribed psychostimulants.Item Pharmacological Assessment of Novel Phenylacetamide as a Sigma 1 Receptor Ligand(2014-05-01) Malik, Maninder; Robert LuedtkeThe symptoms of psychosis have been categorized as positive, negative and cognitive. Traditionally drug discovery in psychiatric disorders has focused on positive symptoms of the disease. However, cognitive impairment is equally prevalent and represents a major impediment to the recovery of patients. Hence, research on the drug discovery and development that can improve overall quality of life of patients with neuropsychiatric conditions is important. The main aim of this project was to evaluate a selective and potent sigma 1 receptor phenylacetamide (LS-1-137) as a potential pharmacotherapeutic agent for treating neuropsychiatric disorders and associated cognitive impairment. The sigma 1 receptor is an endoplasmic reticulum (ER) resident protein located on the interface of ER and mitochondria. The sigma 1 receptor is a 25 KDa protein that shares no amino acid sequence homology with any other known mammalian proteins. The research being done on these novel receptors suggests that rather than being a classical receptor-signaling unit sigma 1 receptors act as a molecular chaperone. Several studies suggest sigma 1 receptor ligands modulate abnormal neurotransmission that contributes to the pathogenesis of several CNS disorders. In recent studies by our laboratory, it was found that our novel sigma 1 receptor ligand, LS-1-137 (developed by our collaborators Mach and colleagues) exhibit neuroprotection both in vitro and in vivo. In this project we further characterized LS-1-137 as a potential treatment option for cognitive and neuropsychiatric disorders. Our fundamental hypothesis is that sigma 1 receptor selective compounds represent a potential neuroprotective pharmacotherapy for treating psychosis and cognitive deficits associated with neuropsychiatric disorders. LS-1-137 was evaluated in a 2, 5-dimethoxy-4-iodoamphetamine (DOI) induced head twitch response (HTR) model and a scopolamine-induced cognition impairment model. Our findings suggest that LS-1-137 attenuates the DOI-induced HTR and alleviates scopolamine-induced impairment in learning. Our in vitro data suggest that LS-1-137 is an agonist at sigma 1 receptors and triggers the release of BDNF from rat astrocytes. Furthermore, rotarod and swim test studies indicated that unlike currently prescribed neuroleptics, LS-1-137 does not compromise the agility or muscular coordination of animals. Therefore, in this dissertation we have assessed a novel pharmacotherapeutic agent that may treat the psychosis and cognitive dysfunction associated with neuropsychiatric disorders.Item SIGMA 1 RECEPTOR SELECTIVE LIGAND ATTENUATES SCOPOLAMINE INDUCED IMPAIRMENT IN LEARNING AND MEMORY(2013-04-12) Malik, ManinderPurpose: Cognitive deficit is seen in patients with Alzheimer's disease, Parkinson's disease, after brain traumatic injury and stroke. Cognitive deficit is mainly due to the alteration in the cholinergic pathway. All currently prescribed therapeutic drugs provide only symptomatic relief and become ineffective as the disease progresses. Therefore, additional novel therapeutic agents need to be developed to slow or stop the progressive loss of memory forming cells. In this project, we will focus on characterizing a ligand selective at sigma 1 receptor for neuroprotection. Methods: A filtration-binding assay was used to characterize the binding properties of novel sigma compound at D2 like dopamine receptors and at sigma receptors. C57BL/6J mice injected with scopolamine were used as our experimental model to evaluate the cognitive properties of test drug. The neuroprotective properties were evaluated using water maze, active avoidance test and novel objet recognition tests. Results: Scopolamine treated animals exhibited impaired learning and memory in water maze and active avoidance test. Animals pre-treated with test drug attenuated the scopolamine-mediated effect. Conclusions: Test drug was able to attenuate the scopolamine-induced impairment in learning and memory.