RESUMEN
Alzheimer's disease (AD) is the most common neuronal disorder that leads to the development of dementia. Until nowadays, some therapies may alleviate the symptoms, but there is no pharmacological treatment. Microdosing lithium has been used to modify the pathological characteristics of the disease, with effects in both experimental and clinical conditions. The present work aimed to analyze the effects of this treatment on spatial memory, anxiety, and molecular mechanisms related to long-term memory formation during the aging process of a mouse model of accelerated aging (SAMP-8). Female SAMP-8 showed learning and memory impairments together with disruption of memory mechanisms, neuronal loss, and increased density of senile plaques compared to their natural control strain, the senescence-accelerated mouse resistant (SAMR-1). Chronic treatment with lithium promoted memory maintenance, reduction in anxiety, and maintenance of proteins related to memory formation and neuronal density. The density of senile plaques was also reduced. An increase in the density of gamma-aminobutyric acid A (GABAA) and α7 nicotinic cholinergic receptors was also observed and related to neuroprotection and anxiety reduction. In addition, this microdose of lithium inhibited the activation of glycogen synthase kinase-3beta (GSK-3ß), the classical mechanism of lithium cell effects, which could contribute to the preservation of the memory mechanism and reduction in senile plaque formation. This work shows that lithium effects in neuroprotection along the aging process are not related to a unique cellular mechanism but produce multiple effects that slowly protect the brain along the aging process.
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Enfermedad de Alzheimer , Litio , Compuestos de Fenilmercurio , Ratones , Femenino , Animales , Litio/farmacología , Litio/uso terapéutico , Placa Amiloide/patología , Glucógeno Sintasa Quinasa 3 beta , Enfermedad de Alzheimer/patología , Envejecimiento/metabolismo , Modelos Animales de EnfermedadRESUMEN
Increase in the quality of life, combined with drug strategies, has been studied as possibilities for improving memory and delaying the onset of neurodegenerative diseases. A previous study published by the group of the authors has shown that microdose lithium and enriched environment can improve memory in both mice and humans. To elucidate this relationship better, this study aimed to evaluate whether the chronic combination of these two strategies could increase healthy aging in Senescence Accelerated Mouse-Prone 8 (SAMP8). Animals were submitted to either one or both of these strategies until the age of 10 months when they were anesthetized and killed and their hippocampus was extracted. The untreated SAMP-8 group exhibited worse memory and reduced neuronal density with greater neurodegeneration and increased amyloid-ß plaque density compared with the control group. Moreover, significant alterations in proteins related to long-term potentiation, such as, synaptophysin and brain-derived neurotrophic factor (BDNF), were observed in this group. The strategies used in the study maintained long-term memory, reduced anxiety, and increased neuroprotection. Both strategies were efficient in reducing neurodegeneration and increasing parameters related to memory maintenance. In many experiments, the combination of the two strategies was more effective in improving healthy aging. This study sheds light on the combination of strategies that choose to improve the quality of life and drugs with low side effects. Moreover, it opens perspectives for a new field of study for healthy aging.
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Aging is a dynamic and progressive process that begins at conception and continues until death. This process leads to a decrease in homeostasis and morphological, biochemical and psychological changes, increasing the individual's vulnerability to various diseases. The growth in the number of aging populations has increased the prevalence of chronic degenerative diseases, impairment of the central nervous system and dementias, such as Alzheimer's disease, whose main risk factor is age, leading to an increase of the number of individuals who need daily support for life activities. Some theories about aging suggest it is caused by an increase of cellular senescence and reactive oxygen species, which leads to inflammation, oxidation, cell membrane damage and consequently neuronal death. Also, mitochondrial mutations, which are generated throughout the aging process, can lead to changes in energy production, deficiencies in electron transport and apoptosis induction that can result in decreased function. Additionally, increasing cellular senescence and the release of proinflammatory cytokines can cause irreversible damage to neuronal cells. Recent reports point to the importance of changing lifestyle by increasing physical exercise, improving nutrition and environmental enrichment to activate neuroprotective defense mechanisms. Therefore, this review aims to address the latest information about the different mechanisms related to neuroplasticity and neuronal death and to provide strategies that can improve neuroprotection and decrease the neurodegeneration caused by aging and environmental stressors.
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It was already shown that microdoses of lithium carbonate (Li2CO3) promoted memory stabilization in humans and mice. Prolonged treatment also reduced neuronal loss and increased the density of the neurotrophin BDNF in transgenic mice for Alzheimer's disease. The aim of this study was to evaluate whether lithium ions affect inflammatory profiles and neuronal integrity in an animal model of accelerated senescence (SAMP-8). Organotypic hippocampal cultures obtained from 11 to 12-month-old SAMP-8 mice were treated with 2 µM, 20 µM and 200 µM Li2CO3. 2 µM Li2CO3 promoted a significant reduction in propidium iodide uptake in the CA2 area of hippocampus, whereas 20 µM promoted neuroprotection in the CA3 and GrDG areas. 200 µM caused an increase in cellular death, showing toxicity. Measured with quantitative PCR, IL-1α, IL-6 and MIP-1B/CCL-4 gene expression was significantly reduced with 20 µM Li2CO3, whereas IL-10 gene expression was significantly increased with the same concentration. In addition, 2 µM and 20 µM Li2CO3 were also effective in reducing the activation of NFkB and inflammatory cytokines densities, as evaluated by ELISA. It is concluded that very low doses of Li2CO3 can play an important role in neuroprotection as it can reduce neuronal loss and neuroinflammation in older individuals.
Asunto(s)
Muerte Celular/efectos de los fármacos , Hipocampo/efectos de los fármacos , Litio/farmacología , Fármacos Neuroprotectores/farmacología , Compuestos de Fenilmercurio/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
BACKGROUND: Alzheimer's disease is mainly characterized by remarkable neurodegeneration in brain areas related to memory formation. This progressive neurodegeneration causes cognitive impairment, changes in behavior, functional disability, and even death. Our group has demonstrated changes in the kallikrein-kinin system (KKS) in Alzheimer's disease (AD) experimental models, but there is a lack of evidence about the role of the KKS in Alzheimer's disease. AIM: In order to answer this question, we evaluated the potential of the kinin B2 receptors (BKB2R) to modify AD characteristics, particularly memory impairment, neurodegeneration, and Aß peptide deposition. METHODS: To assess the effects of B2, we used transgenic Alzheimer's disease mice treated with B2 receptor (B2R) agonists and antagonists, and performed behavioral and biochemical tests. In addition, we performed organotypic hippocampal culture of wild-type (WT) and transgenic (TG) animals, where the density of cytokines, neurotrophin BDNF, activated astrocyte marker S100B, and cell death were analyzed after treatments. RESULTS: Treatment with the B2R agonist preserved the spatial memory of transgenic mice and decreased amyloid plaque deposition. In organotypic hippocampal culture, treatment with B2R agonist decreased cell death, neuroinflammation, and S100B levels, and increased BDNF release. CONCLUSIONS: Our results indicate that the kallikrein-kinin system plays a beneficial role in Alzheimer's disease through B2R activation. The use of B2R agonists could, therefore, be a possible therapeutic option for patients diagnosed with Alzheimer's disease.
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Cell senescence is a process that causes growth arrest and the release of a senescence associated secretory phenotype (SASP), characterized by secretion of chemokines, cytokines, cell growth factors and metalloproteases, leading to a tissue condition that may precipitate cancers and neurodegenerative processes. With the recent pandemic of coronavirus, senolytic drugs are being considered as possible therapeutic tools to reduce the virulence of SARS-CoV-2. In the last few years, our research group showed that lithium carbonate at microdose levels was able to stabilize memory and change neuropathological characteristics of Alzheimer's disease (AD). In the present work, we present evidence that low-dose lithium can reduce the SASP of human iPSCs-derived astrocytes following acute treatment, suggesting that microdose lithium could protect cells from senescence and development of aging-related conditions. With the present findings, a perspective of the potential use of low-dose lithium in old patients from the "high risk group" for COVID-19 (with hypertension, diabetes and chronic obstructive pulmonary disease) is presented.
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Astrocitos/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Compuestos de Litio/uso terapéutico , Neumonía Viral/tratamiento farmacológico , COVID-19 , Células Cultivadas , Evaluación Preclínica de Medicamentos , Humanos , PandemiasRESUMEN
Aging is a multifactorial phenomenon that results in several changes at cellular and molecular levels and is considered the main risk factor for some neurodegenerative diseases. Several evidence show the participation of the kallikrein-kinin system (KKS) in neurodegeneration and this system has been associated with inflammation and immunogenic responses in the central and peripheral systems by the activation of the B1 and B2 receptors. Previous work by our group showed that bradykinin (BK) and the B2 receptor played a possible role in neuroprotection. Therefore, the objective of this study was to evaluate the participation of B2 receptors in cell viability, neuroinflammatory response and neuroplasticity in organotypic hippocampal cultures (OHCs) of 6- and 12-month-old mice. It was observed that activation of the B2 receptor by bradykinin decreased the inflammatory response and increased plasticity in 12-month-old slices. Conversely, there was an increase in the inflammatory response and a decrease in neural plasticity in the 6-month-old slices. In both ages, an increase in cell viability was observed. This data suggests that the function of the kinin B2 receptor in the hippocampus is modulated by age, providing neuroprotective action in old age.
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BACKGROUND AND PURPOSE: Attention training reverses the neurodegeneration and memory loss promoted by infusion of amyloid-ß (Aß) peptide in rats and increases the density of α7 nicotinic ACh receptors (α7nAChRs) in brain areas related to memory. Hence, we aimed to assess the role of α7nAChRs in the memory recovery promoted by attention training. EXPERIMENTAL APPROACH: C57Bl/6 mice were chronically infused with Aß, Aß plus the α7 antagonist methyllycaconitine (MLA), or MLA alone. Control animals were infused with vehicle. Animals were subjected weekly to the active avoidance shuttle box for 4 weeks (attention training). The brain and serum were collected for biochemical and histological analysis. KEY RESULTS: Aß caused cognitive impairment, which was reversed by the weekly training, whereas Aß + MLA also promoted memory loss but with no reversal with weekly training. MLA alone also promoted memory loss but with only partial reversal with the training. Animals infused with Aß alone showed senile plaques in hippocampus, no change in BDNF levels in cortex, hippocampus, and serum, but increased AChE activity in cortex and hippocampus. Co-treatment with MLA increased AChE activity and senile plaque deposition in hippocampus as well as reducing BDNF in hippocampus and serum, suggesting a lack of α7nAChR function leads to a loss of neuroprotection mechanisms. CONCLUSIONS AND IMPLICATIONS: The α7nAChR has a determinant role in memory recovery and brain resilience in the presence of neurodegeneration promoted by Aß peptide. These data support further studies concerning these receptors as pharmacological targets for future therapies.
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Péptidos beta-Amiloides/metabolismo , Memoria , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , NeuroprotecciónRESUMEN
Alzheimer's disease (AD) is associated with a progressive dementia, and there is good evidence that it is more pronounced in individuals that have fewer stimuli during their lives. Environmental stimulation promotes morphological and functional changes in the brain, leading to amplification of cognitive functions, and has been described in humans and animals. In this study, we evaluated the effects of enriched environment (EE) stimulation on spatial memory and senile plaque formation in transgenic mice PDGFB-APPSwInd (TG) that overexpress the human amyloid precursor protein, normally resulting in an increased density of senile plaques. We compared this group of EE stimulated transgenic mice (TG-EE) with an EE stimulated control group of age-matched C57Bl/6 wild type animals (WT-EE). Both groups were exposed to EE stimulation between the ages of 8 and 12 months. As controls of the experiment, there were a group of TG mice not exposed to EE (TG-Ctrl) and a group of WT mice not exposed to EE (WT-Ctrl). The TG-EE group presented improved spatial memory when compared to the TG-Ctrl animals. In addition, the TG-EE group showed a 69.2% reduction in the total density of senile plaques in the hippocampus when compared to the TG-Ctrl group. In this group, the concentration of senile plaques was greater in the dorsal part of the hippocampus, which is linked to spatial localization, and the reduction of this density after the submission to EE was as high as 85.1%. EE stimulation had no effect on the density of amyloid-ß (Aß) oligomers. However, amyloid scavenger receptor class B member 1 (SR-B1) density was significantly decreased in the TG-Ctrl mice, but not in the TG-EE mice, suggesting that cognitive stimulation had an effect on the formation of a cognitive reserve that could prevent the accumulation of senile plaques. It is suggested that the stimulation of old mice by EE for 4 months led to the formation of brain resilience that protected the brain from the deposition of senile plaques, one of the hallmarks of AD, leading to improvement in spatial memory.
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Alzheimer's disease is a chronic and degenerative condition that had no treatment until recently. The current therapeutic strategies reduce progression of the disease but are expensive and commonly cause side effects that are uncomfortable for treated patients. Functional foods to prevent and/or treat many conditions, including neurodegenerative diseases, represent a promising field of study currently gaining attention. To this end, here we demonstrate the effects of pomegranate (Punica granatum) peel extract (PPE) regarding spatial memory, biomarkers of neuroplasticity, oxidative stress and inflammation in a mouse model of neurodegeneration. Male C57Bl/6 mice were chronically infused for 35 days with amyloid-ß peptide 1-42 (Aß) or vehicle (control) using mini-osmotic pumps. Another group, also infused with Aß, was treated with PPE (p.o.- ßA+PPE, 800 mg/kg/day). Spatial memory was evaluated in the Barnes maze. Animals treated with PPE and in the control group exhibited a reduction in failure to find the escape box, a finding that was not observed in the Aß group. The consumption of PPE reduced amyloid plaque density, increased the expression of neurotrophin BDNF and reduced the activity of acetylcholinesterase enzyme. A reduction in lipid peroxidation and in the concentration of the pro-inflammatory cytokine TNF-α was also observed in the PPE group. No hepatic lesions were observed in animals treated with PPE. In conclusion, administration of pomegranate peel extract has neuroprotective effects involving multiple mechanisms to prevent establishment and progression of the neurodegenerative process induced by infusion with amyloid-ß peptide in mice.
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Péptidos beta-Amiloides/farmacología , Frutas , Lythraceae , Enfermedades Neurodegenerativas/prevención & control , Fármacos Neuroprotectores/farmacología , Fitoterapia/métodos , Extractos Vegetales/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Modelos Animales de Enfermedad , Frutas/química , Inflamación/prevención & control , Lythraceae/química , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Enfermedades Neurodegenerativas/patología , Plasticidad Neuronal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacosRESUMEN
The purpose of this investigation was to determine lipid peroxidation markers, physiological stress and muscle damage in elite kayakers in response to a maximum 4-min kayak ergometer test (KE test), and possible correlations with individual 1000m kayaking performances. The sample consisted of twenty-three adult male and nine adult female elite kayakers, with more than three years' experience in international events, who voluntarily took part in this study. The subjects performed a 10-min warm-up, followed by a 2-min passive interval, before starting the test itself, which consisted of a maximum 4-min work paddling on an ergometer; right after the end of the test, an 8 ml blood sample was collected for analysis. 72 hours after the test, all athletes took part in an official race, when then it was possible to check their performance in the on site K1 1000m test (P1000m). The results showed that all lipoproteins and hematological parameters tested presented a significant difference (p≤0.05) after exercise for both genders. In addition, parameters related to muscle damage such as lactate dehydrogenase (LDH) and creatine kinase (CK) presented significant differences after stress. Uric acid presented an inverse correlation with the performance (r = -0.76), while CK presented a positive correlation (r = 0.46) with it. Based on these results, it was possible to verify muscle damage and the level of oxidative stress caused by indoor training with specific ergometers for speed kayaking, highlighting the importance of analyzing and getting to know the physiological responses to this type of training, in order to provide information to coaches and optimize athletic performance.
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Prueba de Esfuerzo , Músculo Esquelético/fisiopatología , Estrés Oxidativo , Deportes , Adulto , Femenino , Humanos , MasculinoRESUMEN
Weekly submission of rats to active avoidance apparatus can be considered a neurostimulation strategy, once it can improve memory and can increase the density of receptors from different neurotransmitter systems in brain areas related to memory. These benefits were observed in rats chronically infused with amyloid-ß peptide. In the present work it is presented that the same benefit for memory was observed in five months old transgenic mice for Alzheimer's disease (TG-PDGFB-APPSw,Ind). However, at this age, no change in density of nicotinic receptors was observed.
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The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer's disease (AD) patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd)20Lms/2J) and their non-transgenic litter mate genetic controls were treated with lithium carbonate (0.25mg/Kg/day in drinking water) for 16 or 8 months starting at two and ten months of age, respectively [corrected]. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer's disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained.
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Enfermedad de Alzheimer/tratamiento farmacológico , Amnesia/prevención & control , Trastornos del Conocimiento/prevención & control , Carbonato de Litio/farmacología , Fármacos Neuroprotectores/farmacología , Placa Amiloide/prevención & control , Administración Oral , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Amnesia/genética , Amnesia/patología , Amnesia/fisiopatología , Animales , Reacción de Prevención/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Esquema de Medicación , Expresión Génica , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/fisiología , Ratones , Ratones Transgénicos , Placa Amiloide/genética , Placa Amiloide/patología , Placa Amiloide/fisiopatologíaRESUMEN
Renal insufficiency can have a negative impact on cognitive function. Neuroinflammation and changes in klotho levels associate with chronic kidney disease (CKD) and may play a role in the development of cognitive impairment (CI). The present study evaluates the correlation of cognitive deficits with neuroinflammation and soluble KLOTHO in the cerebral spinal fluid (CSF) and brain tissue of nephrectomized rats (Nx), with 5/6 renal mass ablation. Nx and sham Munich Wistar rats were tested over 4 months for locomotor activity, as well as inhibitory avoidance or novel object recognition, which started 30 days after the surgery. EMSA for Nuclear factor-κB and MILLIPLEXMAP or ELISA kit were used to evaluate cytokines, glucocorticoid and KLOTHO levels. Nx animals that showed a loss in aversive-related memory and attention were included in the CI group (Nx-CI) (n=14) and compared to animals with intact learning (Nx-M n=12 and Sham n=20 groups). CSF and tissue samples were collected 24 hours after the last behavioral test. The results show that the Nx-groups have increased NF-κB binding activity and tumor necrosis factor-alpha (TNF-α) levels in the hippocampus and frontal cortex, with these changes more pronounced in the Nx-CI group frontal cortex. In addition, the Nx-CI group showed significantly increased CSF glucocorticoid levels and TNF-α /IL-10 ratio compared to the Sham group. Klotho levels were decreased in Nx-CI frontal cortex but not in hippocampus, when compared to Nx-M and Sham groups. Overall, these results suggest that neuroinflammation mediated by frontal cortex NF-κB, TNF-α and KLOTHO signaling may contribute to Nx-induced CI in rats.
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Trastornos del Conocimiento/metabolismo , Glucuronidasa/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Atención , Encéfalo/metabolismo , Trastornos del Conocimiento/etiología , Glucuronidasa/líquido cefalorraquídeo , Glucuronidasa/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Proteínas Klotho , Masculino , Memoria , FN-kappa B/genética , Nefrectomía/efectos adversos , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Immunohistochemistry is a specific and sensitive staining method for detection of several proteins. One important function of this method is to help us on the diagnosis of the presence of specific receptors as the estrogen receptors. The aim of this study was to compare two different methods to evaluate immunohistochemical staining intensity to detect the presence of ER in the nasal mucosa tissue: one using a digital system and the other through conventional direct microscopy observation. Sixty two stained samples were observed and analyzed under optic microscopy by three specialized professionals, who have graded intensity from: absent, mild, moderate and intense staining. Afterwards, an objective measurement was obtained by a relative optical density (ROD) reading, through the MCID 7.0 system of densitometric digital analysis (Inter Focus Imaging LTDA, Linton, England). Subjective and objective classifications were compared under statistical analysis (Kolmogorov-Smirnov and Spearman Correlation Test, p<0.05). We found a positive correlation between the subjective findings of observers and digital analysis in all the categories of beta receptor. For the alpha receptor, there was a correlation only in extreme categories. The subjective evaluations by observers and digital method by measuring the relative optical density show statistically significant correlations in quantifying the estrogen receptors by immunohistochemistry staining. This indicates that both methods show accuracy for the proposed study.
La inmunohistoquímica es un método de tinción específico para la detección de varias proteínas. Este método es importante en el diagnóstico de la presencia de receptores específicos, tales como los receptores de estrógeno. El objetivo de este estudio fue comparar dos métodos diferentes para evaluar la intensidad de la tinción inmunohistoquímica para detectar la presencia de RE en el tejido de la mucosa nasal: el primero utilizando un sistema digital y el segundo a través de la observación directa de microscopía convencional. Tres profesionales especializados observaron sesenta y dos muestras teñidas las que fueron analizadas con microscopio óptico con la siguiente intensidad de tinción: ausente, leve, moderada e intensa. Posteriormente, se obtuvo una medición objetiva a través de lectura de densidad óptica relativa (DOR) del sistema MCID 7.0 de análisis de densitometría digital (Inter Enfoque de imágenes LTDA, Linton, Inglaterra). Clasificaciones subjetivas y objetivas fueron comparadas bajo análisis estadístico (Kolmogorov-Smirnov y prueba de correlación de Spearman, p<0,05). Encontramos una correlación positiva entre los resultados subjetivos de los observadores y el análisis digital en todas las categorías de los receptores beta. Para el receptor alfa, hubo una correlación solamente en categorías extremas. Las evaluaciones subjetivas de los observadores y método digital midiendo la densidad óptica relativa muestran correlaciones estadísticamente significativas en la cuantificación de los receptores de estrógeno por tinción inmunohistoquímica. Por tanto ambos métodos demostraron ser correctos para el estudio propuesto.
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Inmunohistoquímica/métodos , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/ultraestructura , Coloración y Etiquetado , Procesamiento de Imagen Asistido por Computador , Microscopía Electrónica , Estudios ProspectivosRESUMEN
In the central nervous system, the degree of decline in memory retrieval along the aging process depends on the quantity and quality of the stimuli received during lifetime. The cholinergic system modulates long-term potentiation and, therefore, memory processing. This study evaluated the spatial memory, the synaptic plasticity and the density of cholinergic markers in the hippocampi of mice submitted to cognitive stimulation during lifetime or during their aged phase. Male C57Bl/6 mice (2 months old) were exposed to enriched environment during 15 months (EE-15). An age-matched group was left in standard cages during the same period (SC-15). Spatial memory was evaluated using the Barnes maze at 2, 5, 11 and 17 months of age. At the 17-month-old time point, EE-15 mice showed better performance in the spatial memory task (P<0.05), when compared to C-15 mice. Other two groups of mice were left in regular cages until the age of 15 months, and then one of the groups was transferred to an enriched environment for two months (EE-2). The other group was kept in regular cages (C-2). After two months of stimulation, EE-2 showed a significant increase in spatial memory (P<0.01). At the end, brains were extracted and kept at -80°C. Slices were obtained from one hemisphere in a cryostat (20 µm, -18°C) and thaw-mounted on gelatin coated slides. Synaptic densities, cellular bodies, BDNF densities and α4ß2 nicotinic cholinergic receptors (nAChR) were evaluated by immunohistochemistry. Autoradiography for α7 nAChR was conducted using [(125)I]-α-bungarotoxin. The other half of the brains was used for Western blotting analysis of choline acetyltransferase (ChAT) density. There was no difference in synaptophysin or MAP-2 densities, but BDNF was increased in some hippocampal areas of EE-15 and EE-2, in comparison to control groups. In the same way, increases in ChAT and α7 densities, but not in α4ß2, were observed. Both cognitive stimuli during lifetime or during the aged phase improved spatial memory of mice. No difference in structural plasticity was observed, but the maintenance of memory can be due to improvement in long-term potentiation functionality in the hippocampus, modulated, at least, by BDNF and the cholinergic system.
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Envejecimiento/fisiología , Neuronas Colinérgicas/fisiología , Cognición/fisiología , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/prevención & control , Plasticidad Neuronal/fisiología , Animales , Conducta Animal/fisiología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/fisiopatología , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Receptores Nicotínicos/metabolismo , Sinaptofisina/metabolismoRESUMEN
A lower incidence of dementia in bipolar patients treated with lithium has been described. This metal inhibits the phosphorylation of glycogen-synthase-kinase 3-α and ß, which are related to amyloid precursor protein processing and tau hyperphosphorylation in pathological conditions, respectively. Following the same rationale, a group just found that lithium has disease-modifying properties in amnestic mild cognitive impairment with potential clinical implications for the prevention of Alzheimer's Disease (AD) when a dose ranging from 150 to 600 mg is used. As lithium is highly toxic in regular doses, our group evaluated the effect of a microdose of 300 µg, administered once daily on AD patients for 15 months. In the evaluation phase, the treated group showed no decreased performance in the mini-mental state examination test, in opposition to the lower scores observed for the control group during the treatment, with significant differences starting three months after the beginning of the treatment, and increasing progressively. This data suggests the efficacy of a microdose lithium treatment in preventing cognitive loss, reinforcing its therapeutic potential to treat AD using very low doses.
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Adyuvantes Inmunológicos/uso terapéutico , Enfermedad de Alzheimer/complicaciones , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Cloruro de Litio/uso terapéutico , Anciano , Análisis de Varianza , Método Doble Ciego , Femenino , Humanos , Masculino , Escalas de Valoración PsiquiátricaRESUMEN
It is already known that progressive degeneration of cholinergic neurons in brain areas such as the hippocampus and the cortex leads to memory deficits, as observed in Alzheimer's disease. This work verified the effects of the infusion of amyloid-ß (Aß) peptide associated to an attentional rehearsal on the density of α7 nicotinic cholinergic receptor (nAChR) in the brain of male Wistar rats. Animals received intracerebroventricular infusion of Aß or vehicle (control - C) and their attention was stimulated weekly (Stimulated Aß group: S-Aß and Stimulated Control group: SC) or not (Non- Stimulated Aß group: N-SAß and Non-Stimulated Control group: N-SC), using an active avoidance apparatus. Conditioned avoidance responses (CAR) were registered. Chronic infusion of Aß caused a 37% reduction in CAR for N-SAß. In S-Aß, this reduction was not observed. At the end, brains were extracted and autoradiography for α7 nAChR was conducted using [125I]-α-bungarotoxin. There was an increase in α7 density in hippocampus, cortex and amygdala of SAß animals, together with the memory preservation. In recent findings from our lab using mice infused with Aß and the α7 antagonist methyllycaconitine, and stimulated weekly in the same apparatus, it was observed that memory maintenance was abolished. So, the increase in α7 density in brain areas related to memory might be related to a participation of this receptor in the long-lasting change in synaptic plasticity, which is important to improve and maintain memory consolidation.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Atención/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Fragmentos de Péptidos/farmacología , Receptores Nicotínicos/metabolismo , Análisis de Varianza , Animales , Autorradiografía , Reacción de Prevención/efectos de los fármacos , Bungarotoxinas/farmacocinética , Humanos , Isótopos de Yodo/farmacocinética , Masculino , Unión Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Factores de Tiempo , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
BACKGROUND: There is evidence that the nasal mucosa is affected by estrogen influence. Some authors have already detected estrogen receptors (ER) in the nasal mucosa. However, there doesn't seem to be a consensus about the concentration and distribution of the ER or the possible influence of hormonal contraceptives in the nasal mucosa. OBJECTIVE: The study was conducted to evaluate the influence of oral contraceptives on the distribution and concentration of estrogenic receptors in nasal mucosa. STUDY DESIGN: Two groups of 32 women with regular menstrual cycles were selected. One group of women was taking oral contraceptives and the other was not. Samples of mucosa of inferior nasal turbinate were analyzed by immunohistochemical staining for alpha and beta ER. RESULTS: The use of oral contraceptives induced a decrease of beta-receptors only in lamina propria cells. In both groups, there was a predominance of beta-receptors. CONCLUSION: Women who took oral contraceptives showed a decrease of beta-receptors in some cells of the lamina propria. These findings show us the possibility of effects of contraceptive pills on the cells such as fibroblasts, mast cells, plasmocytes, and other inflammatory cells.