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Finasteride, a 5α-Reductase inhibitor, is used to treat male pattern baldness and benign prostatic hyperplasia. Several clinical studies show that chronic finasteride treatment induces persistent depression, suicidal thoughts and cognitive impairment and these symptoms are persistent even after its withdrawal. Previous results from our lab showed that repeated administration of finasteride for six days induces depression-like behavior. However, whether short-term finasteride administration induces anxiety-like behavior and memory impairment and alters synaptic plasticity are not known, which formed the basis of this study. Finasteride was administered to 2-2.5 months old male Wistar rats for six days and subjected to behavioral evaluation, biochemical estimation and synaptic plasticity assessment. Anxiety-like behavior was evaluated in the elevated plus maze (EPM), open field test (OFT), light/dark test (LDT), and novelty suppressed feeding test (NSFT), and learning and memory using novel object recognition test (NORT) and novel object location test (NOLT) and depression-like behavior in the sucrose preference test (SPT). Synaptic plasticity in the hippocampal Schaffer collateral-CA1 was evaluated using slice field potential recordings. Plasma corticosterone levels were estimated using ELISA. Finasteride administration induced anxiety-like behavior in the EPM, OFT, LDT and NSFT, and depression-like behavior in the SPT. Further, finasteride induced hippocampal dependent spatial learning and memory impairment in the NOLT. In addition, finasteride decreased basal synaptic plasticity and long-term potentiation (LTP) in the hippocampus. A trend of increased plasma corticosterone levels was observed following repeated finasteride administration. These results indicate the potential role of corticosterone and synaptic plasticity in finasteride-induced effects and further studies will pave way for the development of novel neurosteroid-based therapeutics in neuropsychiatric diseases.
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Inhibidores de 5-alfa-Reductasa , Ansiedad , Corticosterona , Depresión , Finasterida , Plasticidad Neuronal , Ratas Wistar , Animales , Masculino , Finasterida/farmacología , Finasterida/administración & dosificación , Finasterida/efectos adversos , Inhibidores de 5-alfa-Reductasa/farmacología , Inhibidores de 5-alfa-Reductasa/administración & dosificación , Inhibidores de 5-alfa-Reductasa/efectos adversos , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Ansiedad/inducido químicamente , Ansiedad/fisiopatología , Corticosterona/sangre , Ratas , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
Gallic acid (GA) is a natural polyhydroxyphenolic compound with antioxidant, antimutagenic, anti-inflammatory, and antineoplastic activities. Cisplatin (CPT) is a platinum-based chemotherapeutic drug, and it is the treatment of choice for breast, ovarian, testicular, head, and neck cancers. However, the use of anticancer drugs has undesirable effects on patients due to associated toxicities. Thus, it is necessary to search for alternatives that reduce unintended side effects and enhance anticancer potential. The use of natural compounds with the conventional chemotherapeutic drug is a new aspect of cancer therapy. In the present study, we evaluated the ability of GA in the modulation of anticancer effects of CPT in human breast adenocarcinoma cells (MCF-7) by performing MTT, apoptosis, clonogenic cell survival, and micronucleus assays. GA and CPT showed significant cytotoxic activities in MCF-7 cells in a dose-dependent manner. In combination therapy (GA 2.5, 5.0, and 10 µg/mL + CPT10 µg/mL), GA synergistically reduced the MCF-7 cell viability in contrast to the individual therapies. Cancer cells death by GA is through the induction of apoptosis as observed in the acridine orange and ethidium bromide dual staining method. The frequency of micronuclei (MN) was decreased significantly (P < 0.001) in combinational therapy, possibly reducing the risk of chemotherapy-induced MN. Moreover, GA in mono or combinational therapy did not induce any cytotoxic effects in normal breast epithelial cells (MCF-10A). GA did not show any significant difference in colony inhibition compared to CPT. This outcome shows its differential effects in normal and cancerous cells. Hence, the combination GA with chemotherapeutic drugs could represent a promising alternative therapy in cancer treatment with minimal side effects.
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One of the characteristic features of adolescence is risk-taking behavioural traits. Uncontrolled risk-taking without proper assessment may have harmful impact on mental health later in life. Therefore, it is essential to identify it early for the preventable health problems. In the present study, we have designed a novel paradigm, viz. Risky Decision-taking Task (RDTT), to evaluate the spontaneous risk-taking behavioural repertoire in adolescent rodents. The task was designed based on both risk and cognitive factors. To validate and compare the risk-taking tendency, we have used early maternal separation and isolation (MS) stress model, as it is known to increase anxiety and curiosity-like behaviour at adolescence. We have used Sprague-Dawley rats of both sexes. Rats were exposed to MS stress for 10 days daily for six hours during stress hyporesponsive period (SHRP) from postnatal day 4-13. These rats were subjected to RDTT during adolescence. This task is a reward-based task where the latency to collect reward in the presence or absence of a risk factor is assessed. It consists of habituation, training to find the location of small and large rewards, reward preference for small and large reward and testing period under risky situation. Rats were trained individually to retrieve the valuation-based rewards under the risky, but innate aversive environments. The results from RDTT showed that as compared to controls, MS rats from both sexes showed reduced latency to collect large reward in the presence of a risk element and a reduced risk-index which is indicative of a higher risk-taking tendency in these rats. In addition, MS rats showed a trend towards anxiety-like behaviour as compared to controls in the Light-Dark Test. These results together show decreased risk latency for the large reward and reduced risk assessment in MS rats which is suggestive of more risk-taking tendency in these rats. Thus, we propose that RDTT paradigm can be used to evaluate the spontaneous risk-taking behavioural repertoire based on innate, spontaneous aversion and cognitive factors in rats.
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Toma de Decisiones , Estrés Psicológico , Animales , Femenino , Masculino , Ratas , Privación Materna , Ratas Sprague-Dawley , Recompensa , Asunción de RiesgosRESUMEN
Chronic diabetic conditions have been associated with certain cerebral complications, that include neurobehavioral dysfunctional patterns and morphological alterations of neurons, especially the hippocampus. Neuroanatomical studies done by the authors have shown decreased total dendritic length, intersections, dendritic length per branch order and nodes in the CA1 hippocampal region of the diabetic brain as compared to its normal control group, indicating reduced dendritic arborization of the hippocampal CA1 neurons. Epigenetic alterations in the brain are well known to affect age-associated disorders, however its association with the evolving diabetes-induced damage in the brain is still not fully understood. DNA hypermethylation within the neurons, tend to silent the gene expression of several regulatory proteins. The findings in the study have shown an increase in global DNA methylation in palmitic acid-induced lipotoxic Neuro-2a cells as well as within the diabetic mice brain. Inhibiting DNA methylation, restored the levels of HSF1 and certain HSPs, suggesting plausible effect of DNMTs in maintaining the proteostasis and synaptic fidelity. Neuroinflammation, as exhibited by the astrocyte activation (GFAP), were further significantly decreased in the 5-azadeoxycytidine group (DNMT inhibitor). This was further evidenced by decrease in proinflammatory cytokines TNFâº, IL-6, and mediators iNOS and Phospho-NFkB. Our results suggest that changes in DNA methylation advocate epigenetic dysregulation and its involvement in disrupting the synaptic exactitude in the hippocampus of diabetic mice model, providing an insight into the pathophysiology of diabetes-induced neuroepigenetic changes.
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Disfunción Cognitiva , Diabetes Mellitus Experimental , Animales , Ratones , Metilación de ADN/genética , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Encéfalo , Disfunción Cognitiva/genética , Citocinas , HipocampoRESUMEN
BACKGROUND: Allopregnanolone (3α, 5α-tetrahydroprogesterone) is an inhibitory neurosteroid synthesized from progesterone via 5α-reductase activity in the brain and has anxiolytic, antidepressant, sedative, anticonvulsant, and analgesic activity. Altered levels of allopregnanolone cause anxiety, depression, premenstrual syndrome, and psychiatric disorders. Although allopregnanolone exerts most of its actions by modulating GABAA receptor, NMDA receptor, BDNF expression, and PXR activity, a recent study showed its effects are blocked by mifepristone on lordosis behavior which indicates the involvement of progestin or glucocorticoid receptors in the effects of allopregnanolone since mifepristone blocks both these receptors. However, whether these receptors are involved in acute anxiolytic or antidepressant-like effects is unknown. METHODS: Adult male Wistar rats were used to study whether the prior administration of mifepristone would alter the effects of allopregnanolone in the elevated plus maze (EPM) and forced swim test (FST) was evaluated. RESULTS: 10 mg/Kg dose of allopregnanolone increased percent open arm entries in the EPM, whereas 3 mg/Kg dose of allopregnanolone decreased percent immobility in the FST. Mifepristone administration resulted in a U-shaped response in the FST (with 1 mg/Kg, s.c., decreasing the immobility time) without significantly impacting the behavior in the EPM. In combination studies, mifepristone blocked the anxiolytic and antidepressant effects of allopregnanolone. CONCLUSION: The current study provides evidence for the first time that progestin or glucocorticoid receptors are involved in the acute anxiolytic and antidepressant effects of allopregnanolone. Understanding the mechanism of action of allopregnanolone will help us design better therapeutic strategies to treat neuropsychiatric diseases such as depression and anxiety.
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Mifepristone is a non-selective progesterone (PR), glucocorticoid (GR), and androgen receptor (AR) antagonist with antidepressant and anxiolytic effects. The dose and duration of mifepristone administration vary in rodent preclinical studies to evaluate depression-like and anxiety-like behavior. This review summarizes the findings so far and attempts to reconcile some of the differences in the results. While a few studies assessed basal depression- and anxiety-like behavior, several studies have used mifepristone in conjunction with stress, corticosterone/dexamethasone (after adrenalectomy), or progesterone administration. The effect of mifepristone on depression-like behavior appears to depend not only on the dose and duration of administration but also on the intensity or type of stress. In addition, the anxiolytic effects may depend on the species and strain of the experimental animals. More reports assess antidepressant-like or anxiolytic-like effects following acute than chronic administration. These effects are dependent on the paradigms and the nature of stressors. Most mifepristone studies implicate the role of GRs, yet only two reports have confirmed its role using a genetic approach, whereas none implicate the role of PRs/ARs. There are several novel selective GR antagonists whose effects on depression- and anxiety-like behavior are yet to be studied. Future studies could aim to confirm the role of GRs and evaluate the contribution of PRs/ARs to the effects of mifepristone. Such studies will contribute to a better understanding of depression, anxiety, and other mood disorders and develop novel strategies, particularly for treatment-resistant conditions.
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Ansiolíticos , Mifepristona , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Glucocorticoides , Mifepristona/farmacología , Progesterona , Receptores de Glucocorticoides , RoedoresRESUMEN
The subiculum, an important structure of the hippocampal formation, regulates spatial information processing, social cognition, and affective behavior. Earlier we demonstrated deficits in sociability and social novelty as a measure of social cognition in ventral subicular lesioned (VSL) rats. The present study investigated empathy-like pro-social behavior and the associated affective states in VSL rats. The ability of free rats to release trapped cagemates was assessed using a modified door-opening empathy task.The rat pairs (free rat and the trapped cagemate) used were from the same group and tested for eight days to assess the pro-social behavior displayed by the free rats. The controlfree rats learned to open the door quickly to release the trapped cagemate and both the rats displayed social responses by emitting 'hedonic' calls (50-kHz ultrasonic vocalizations) while playing after the release. The VSLfree rats, however, were less exploratory, displayed apathy towards the trapped cagemate, demonstrated freezing behavior following door-opening and did not interact with the cagemate even after its release. These findings indicate deficits of social motivation and reinforcement learning associated with lesions in possibly both the rats. In addition, the VSL rat pairs elicited more 22-kHz 'alarm' calls and fewer 50-kHz 'hedonic' calls highlighting the lesion-induced alterations of contextual processing and threat perception abilities. In conclusion, VSL led to significant pro-social deficits implicating the role of ventral subiculum in social cognition and empathy. More studies are needed to substantiate whether the subiculum is implicated in social deficits associated with psychiatric conditions such as autism spectrum disorder.
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Trastorno del Espectro Autista , Empatía , Animales , Trastorno del Espectro Autista/patología , Conducta Animal/fisiología , Hipocampo/patología , Ratas , Ratas Wistar , Conducta Social , Vocalización AnimalRESUMEN
Over the years, the advancement of radio diagnostic imaging tools and techniques has radically improved the diagnosis of different pathophysiological conditions, accompanied by increased exposure to low-dose ionizing radiation. Though the consequences of high dose radiation exposure on humans are very well comprehended, the more publicly relevant effects of low dose radiation (LDR) (≤100 mGy) exposure on the biological system remain ambiguous. The central nervous system, predominantly the developing brain with more neuronal precursor cells, is exceptionally radiosensitive and thus more liable to neurological insult even at low doses, as shown through several rodent studies. Further molecular studies have unraveled the various inflammatory and signaling mechanisms involved in cellular damage and repair that drive these physiological alterations that lead to functional alterations. Interestingly, few studies also claim that LDR exerts therapeutic effects on the brain by initiating an adaptive response. The present review summarizes the current understanding of the effects of low dose radiation at functional, cellular, and molecular levels and the various risks and benefits associated with it based on the evidence available from in vitro, in vivo, and clinical studies. Although the consensus indicates minimum consequences, the overall evidence suggests that LDR can bring about considerable neurological effects in the exposed individual, and hence a re-evaluation of the LDR usage levels and frequency of exposure is required.
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Conducta Animal/efectos de la radiación , Encéfalo/efectos de la radiación , Síndromes de Neurotoxicidad/etiología , Dosis de Radiación , Exposición a la Radiación/efectos adversos , Traumatismos por Radiación/etiología , Radiación Ionizante , Animales , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Relación Dosis-Respuesta en la Radiación , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/fisiopatología , Traumatismos por Radiación/metabolismo , Traumatismos por Radiación/patología , Traumatismos por Radiación/fisiopatología , Medición de Riesgo , Factores de Riesgo , Transducción de Señal/efectos de la radiaciónRESUMEN
Ambient light influences our mood, behavior, and cognition. Phototherapy has been considered as an effective non-pharmacological intervention strategy in the restoration of cognitive functions following central nervous system insults. However, the cellular and molecular underpinnings of phototherapy-mediated functional recovery are yet to be studied. The present study examines the effectiveness of short photoperiod regime (SPR; 6:18-h light:dark cycle) in restoring the cognitive functions in ventral subicular lesioned rats. Bilateral ventral subicular lesion (VSL) resulted in significant impairment of spatial navigational abilities when tested in the Morris water maze (MWM) task. Further, VSL resulted in reduced expression of glucocorticoid receptors (GRs) and activity-regulated cytoskeletal (Arc) protein and suppression of neurogenesis in the hippocampus. VSL also suppressed the magnitude of long-term potentiation (LTP) in the hippocampal Schaffer collateral-CA1 synapses. However, exposure to SPR for 21 days showed significant restoration of spatial performance in the MWM task as the ventral subicular lesioned rats could deploy higher cognitive allocentric navigational strategies to reach the hidden platform. Further, SPR resulted in enhanced expression of hippocampal GR and Arc protein and neurogenesis but not hippocampal LTP suggestive of appropriate need-based SPR intervention. In conclusion, the study demonstrates the effectiveness of SPR in establishing functional recovery as well as the possible molecular and cellular basis of cognitive recovery in a rat model of neurodegeneration. Such studies provide a framework in understanding the efficacy of non-pharmacological strategies in establishing functional recovery in neurodegenerative conditions.
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Hipocampo/metabolismo , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Fotoperiodo , Receptores de Glucocorticoides/metabolismo , Aprendizaje Espacial/fisiología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Hipocampo/efectos de los fármacos , Ácido Iboténico/farmacología , Masculino , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The blood-brain barrier (BBB) is composed of a layer of endothelial cells that is interspersed with a series of tight junctions and characterized by the absence of fenestrations. The permeability of this barrier is controlled by junctions such as tight junctions and adherent junctions as well as several cells such as astrocytes, pericytes, vascular endothelial cells, neurons, microglia, and efflux transporters with relatively enhanced expression. It plays a major role in maintaining homeostasis in the brain and exerts a protective regulatory control on the influx and efflux of molecules. However, it proves to be a challenge for drug delivery strategies that target brain diseases like Dementia, Parkinson's Disease, Alzheimer's Disease, Brain Cancer or Stroke, Huntington's Disease, Lou Gehrig's Disease, etc. Conventional modes of drug delivery are invasive and have been known to contribute to a "leaky BBB", recent studies have highlighted the efficiency and relative safety of receptor-mediated drug delivery. Several receptors are exhibited on the BBB, and actively participate in nutrient uptake, and recognize specific ligands that modulate the process of endocytosis. The strategy employed in receptor-mediated drug delivery exploits this process of "tricking" the receptors into internalizing ligands that are conjugated to carrier systems like liposomes, nanoparticles, monoclonal antibodies, enzymes etc. These in turn are modified with drug molecules, therefore leading to delivery to desired target cells in brain tissue. This review comprehensively explores each of those receptors that can be modified to serve such purposes as well as the currently employed strategies that have led to increased cellular uptake and transport efficiency.
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Barrera Hematoencefálica/efectos de los fármacos , Encefalopatías/tratamiento farmacológico , Fármacos del Sistema Nervioso Central/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Receptores de Superficie Celular/metabolismo , Animales , Transporte Biológico , Barrera Hematoencefálica/metabolismo , Encefalopatías/metabolismo , Encefalopatías/patología , Humanos , Ligandos , PermeabilidadRESUMEN
OBJECTIVE: Neurosteroids are known to exert diverse functions in the brain. 5α-reductase (5α-R), a rate-limiting enzyme involved in the biosynthesis of neurosteroids is inhibited by finasteride. Clinical studies suggest that administration of finasteride causes the emergence of affective symptoms and cognitive dysfunction. Modeling this in rats would provide an opportunity to understand the mechanisms. Accordingly, in the present study, we evaluated the effects of repeated finasteride administration on spatial learning and memory in the partially baited radial arm maze task (RAM) and social cognitive behavior in the social interaction test. Further, to initiate the quest to understand the mechanisms underlying the effects of finasteride, in a separate group of animals, acetylcholinesterase (AChE) activity in the frontal cortex, hippocampus, septum and striatum was estimated. METHODS: 2 months old male Wistar rats were trained to learn a partially baited radial arm maze task (four trials per day till they reach a choice accuracy of 80 %). Following this, rats were administered with either vehicle (HPßCD) or finasteride (30 or 100 mg/Kg, s.c.) for 7 days and then subjected to retention test on the eighth day. To evaluate the social cognition, finasteride was administered for 7 days, followed by social interaction test on the eighth day. All the sessions were video-recorded and analyzed using Noldus Ethovision XT™ software. Following finasteride administration, on the eighth day, rats were euthanized, and AChE activity was estimated by modified Ellman's method. RESULTS: Finasteride (100 mg/Kg, s.c.) administration decreased the percent correct choice during the retention trial of the RAM task. This was paralleled by an increase in the number of total number of errors and reference memory errors. In the social interaction test, finasteride (100 mg/Kg, s.c.) administration decreased the time spent with the rat compared to the object, implying decreased sociability and diminished social preference evidenced by similar time spent with the novel and familiar rat. Reduced AChE activity was observed in the frontal cortex, hippocampus and septum. CONCLUSION: Our study provides evidence that repeated administration of finasteride decreases social interaction and results in cognitive deficits, potentially through a cholinergic mechanism. Further studies are required to understand the exact link between the cognitive effects and the cholinergic system. A deeper probe of the current findings holds promise for the development of novel neurosteroid-based therapeutics to treat affective and cognitive disorders.
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Disfunción Cognitiva , Neuroesteroides , Acetilcolinesterasa , Animales , Colinérgicos , Disfunción Cognitiva/inducido químicamente , Finasterida/farmacología , Masculino , Ratas , Ratas WistarRESUMEN
Exposure to chronic stress precipitates depression and anxiety. Stress-induced responses are differentially regulated by the prefrontal cortex (PFC) and basolateral amygdala (BLA). For instance, repeated stress leads to hypertrophy of BLA, resulting in the emergence of affective symptoms. Chronic stress-induced changes in the metabolism of monoamines are central in the manifestation of affective symptoms. Interestingly, BLA via its reciprocal connections modulates prefrontal cortical monoaminergic responses to acute stress. However, the effects of BLA inactivation on chronic stress-induced affective behaviors and monoaminergic changes in the PFC are relatively unknown. Thus, we hypothesized that inactivation of BLA might prevent chronic immobilization stress (CIS)-induced depressive-, anxiety-like behaviors, and associated monoaminergic alterations in the prelimbic (PrL) and anterior cingulate cortex (ACC) subregions of PFC. We used two different BLA silencing strategies, namely ibotenic acid lesion and reversible temporary inactivation using lidocaine. We found that CIS precipitates depressive- and anxiety-like behaviors. Further, CIS-induced negative affective behaviors were associated with decreased levels of 5-HT, DA, and NE, and increased 5-HIAA/5-HT, DOPAC + HVA/DA, and MHPG/NE ratio in the PrL and ACC, suggesting enhanced metabolism. Interestingly, BLA lesion prior to CIS blocked the emergence of depressive- and anxiety-like behaviors. Moreover, the lesion of BLA prior to CIS was sufficient to prevent alterations in levels of monoamines and their metabolites in the PrL and ACC. Thereafter, we evaluated whether the effects of BLA lesion could be mirrored by temporary inactivation of BLA, specifically during stress. Remarkably, temporary inactivation of BLA during stress recapitulated the effects of lesion. Our results have implications for understanding the role of BLA in chronic stress-induced metabolic alterations in prefrontal cortical monoaminergic systems, and associated mood and anxiety disorders. The current study supports the hypothesis that combating amygdalar hyperactivity might be a viable strategy for the management of stress and associated affective disorders.
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Complejo Nuclear Basolateral/metabolismo , Monoaminas Biogénicas/metabolismo , Inmovilización/psicología , Trastornos del Humor/terapia , Corteza Prefrontal/metabolismo , Estrés Psicológico/psicología , Estrés Psicológico/terapia , Animales , Ansiedad/psicología , Conducta Animal , Depresión/etiología , Depresión/psicología , Ácido Iboténico , Lidocaína , Masculino , Trastornos del Humor/metabolismo , Trastornos del Humor/patología , Actividad Motora , Ratas , Ratas Wistar , Natación/psicologíaRESUMEN
OBJECTIVE: The objective of this study is to evaluate the effects of radiotherapy doses on mineral density and percentage mineral volume of human permanent tooth enamel. MATERIALS AND METHODS: Synchrotron radiation Xray microcomputed tomography (SRµCT) and microhardness testing were carried out on 8 and 20 tooth samples, respectively. Enamel mineral density was derived from SRµCT technique using ImageJ software. Microhardness samples were subjected to Vickers indentations followed by calculation of microhardness and percentage mineral volume values using respective mathematical measures. Data were analyzed using paired t-test at a significance level of 5%. Qualitative analysis of the enamel microstructure was done with two-dimensional projection images and scanned electron micrographs using µCT and field emission scanning electron microscopy, respectively. RESULTS: Vickers microhardness and SRµCT techniques showed a decrease in microhardness and an increase in mineral density, respectively, in postirradiated samples. These changes were related to mineral density variation and alteration of hydroxyapatite crystal lattice in enamel surface. Enamel microstructure showed key features such as microporosities and loss of smooth homogeneous surface. These indicate tribological loss and delamination of enamel which might lead to radiation caries. CONCLUSIONS: Tooth surface loss might be a major contributing factor for radiation caries in head-and-neck cancer patients prescribed to radiotherapy. Such direct effects of radiotherapy cause enamel abrasion, delamination, and damage to the dentinoenamel junction. Suitable measures should, therefore, be worked out to protect nontarget oral tissues such as teeth while delivering effective dosages to target regions.
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Esmalte Dental/efectos de la radiación , Neoplasias de Cabeza y Cuello/radioterapia , Traumatismos por Radiación/etiología , Desmineralización Dental/etiología , Esmalte Dental/ultraestructura , Dureza/efectos de la radiación , Neoplasias de Cabeza y Cuello/patología , Humanos , Técnicas In Vitro , Microscopía Electrónica de Rastreo/métodos , Traumatismos por Radiación/patología , Propiedades de Superficie , Desmineralización Dental/patología , Microtomografía por Rayos X/métodosRESUMEN
RATIONALE: Anxiety is one of the most comorbid conditions with major depressive disorder (MDD). Depression-associated anxiety often stems from the dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its altered regulation by the amygdala. Furthermore, MDD is associated with altered glutamatergic processing leading to anxiety and impaired regulation of the HPA axis. Recent studies have demonstrated that N-acetyl cysteine (NAC), a pleiotropic drug, exerts antidepressant-like effect by modulation of hippocampal functions, periterminal release of glutamate, and/or redox systems. However, the effects of NAC on depression-associated anxiety, HPA axis hyperactivity, and amygdalar dysfunctions are relatively unknown. OBJECTIVES: Accordingly, we evaluated the effect of NAC on neonatal clomipramine (CLI)-induced adulthood anxiety and accompanying changes in plasma corticosterone levels, amygdalar volumes, neuronal/glial densities, levels of monoamines, and their metabolites in the amygdalar complex. RESULTS: We found that chronic treatment with NAC reverses CLI-induced anhedonia and enhanced anxiety. Interestingly, attenuation of CLI-associated anxiety in NAC-treated rats were accompanied by a reversal of adrenal and spleen hypertrophy, and normalization of enhanced plasma corticosterone levels, indicating improved HPA axis functioning. Furthermore, NAC treatment was sufficient to reverse volumetric hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. The effects of NAC in the reversal of CLI-induced impairments were similar to that of fluoxetine (FLX). CONCLUSIONS: We suggest that beneficial effects of NAC on antidepressive- and antianxiety-like behaviors are at least in part mediated via restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that NAC might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.
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Acetilcisteína/administración & dosificación , Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Depuradores de Radicales Libres/administración & dosificación , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/metabolismo , Ansiedad/psicología , Corticosterona/metabolismo , Depresión/metabolismo , Depresión/psicología , Esquema de Medicación , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Resultado del TratamientoRESUMEN
Major depressive disorder (MDD) is associated with enhanced anxiety and reduced reward processing leading to impaired cognitive flexibility. These pathological changes during depression are accompanied by dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its impaired regulation by the amygdala. Notably, the electrical stimulation of brain reward areas produces an antidepressant effect in both MDD patients and animal models of depression. However, the effects of chronic electrical self-stimulation of lateral hypothalamus - medial forebrain bundle (LH-MFB) on depression-associated anxiety and accompanying changes in plasma corticosterone levels, structural, and neurochemical alterations in the amygdala are unknown. Here, we used the neonatal clomipramine (CLI) model of depression. During adulthood, neonatal CLI and vehicle administered rats were subjected to bilateral electrode implantation at LH-MFB and trained to receive intracranial self-stimulation (ICSS) for 14 days. Rats were then tested for anhedonic and anxiety-like behaviors, followed by estimation of plasma corticosterone levels, assessment of amygdalar volumes and neuronal/glial numbers, levels of monoamines and their metabolites in the amygdala. We found that chronic ICSS of LH-MFB reverses CLI-induced anhedonia and anxiety. Interestingly, amelioration of CLI-induced enhanced anhedonia and anxiety in ICSS rats was associated with partial reversal of enhanced plasma corticosterone levels, hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. We suggest that beneficial effects of ICSS on CLI-induced anxiety at least in part mediated by the restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that brain stimulation rewarding experience might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.
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Amígdala del Cerebelo/patología , Antidepresivos Tricíclicos , Ansiedad/inducido químicamente , Encéfalo/fisiología , Clomipramina , Estimulación Eléctrica , Recompensa , Amígdala del Cerebelo/efectos de los fármacos , Animales , Animales Recién Nacidos , Ansiedad/etiología , Ansiedad/psicología , Monoaminas Biogénicas/metabolismo , Corticosterona/sangre , Depresión , Modelos Animales de Enfermedad , Electrodos Implantados , Femenino , Masculino , Embarazo , Ratas , Ratas Wistar , AutoestimulaciónRESUMEN
AIM: To evaluate the antimicrobial, toxicity and cleaning effectiveness of ethylenediaminetetraacetic acid (EDTA) and maleic acid (MA) alone and combined with cetrimide (CTR). METHODOLOGY: Cytotoxic and genotoxic effects were assessed on Chinese hamster cells V79 using the MTT, clonogenic and micronucleus assays, respectively. The bacterial inhibitory and bactericidal concentrations (MIC and MBC, respectively) were determined on a strain of Enterococcus faecalis. Antimicrobial tests were performed on a biofilm model after treatment with the chelating agents by using a biofilm eradication concentration (MBEC) and confocal laser scanning microscope (CLSM) assays. Quantification of cell biomass and percentage of live and dead cells in the biomass were assessed for each group. The percentage reduction of accumulated hard-tissue debris (AHTD) after root canal preparation and final irrigation protocols was evaluated by micro-CT. Statistical tests of one-way analysis of variance (anova), Bonferroni test, Kruskal-Wallis test, Dunn's multiple comparison test and Wilcoxon matched-pairs signed-rank tests were used. RESULTS: Cetrimide alone as well as in combination with EDTA and MA at dilutions of 1/10 and 1/100 was significantly more toxic as compared to untreated controls (P < 0.001). All tested mixtures were nontoxic at a dilution of 1/1000. EDTA retained a weak inhibitory and bactericidal effect against planktonic cells, whilst MA inhibited cells growth and killed 99.9% of the cells when diluted. CTR revealed the most prominent effect, being inhibitory and bactericidal, also when diluted. Cetrimide alone or combined with EDTA was able to remove, respectively, 40% (P < 0.01) and 60% (P < 0.001) of the entire biomass after 1 min. Conversely, MA alone and in combination with CTR did not have a significant effect on biomass reduction. After final irrigation, the AHTD volume was significantly decreased in all groups (P < 0.05). EDTA + CTR and MA + CTR were associated with a significant reduction in the percentage of AHTD on the entire root canal compared to the same solutions without surfactant. CONCLUSIONS: 7% MA was less cytotoxic in comparison with 17% EDTA. The addition of cetrimide to EDTA and MA removed accumulated hard-tissue debris effectively from the canal walls and increased their antimicrobial activity when compared to the same solutions without detergents.
Asunto(s)
Antiinfecciosos , Irrigantes del Conducto Radicular , Animales , Quelantes , Cricetinae , Cavidad Pulpar , Ácido Edético , Preparación del Conducto Radicular , Hipoclorito de SodioRESUMEN
Depression is highly comorbid with anxiety disorders and associated with profound cognitive impairment. Moreover, cognitive deficits associated with hippocampal dysfunction are central in depression and anxiety disorders. Furthermore, depression is accompanied by glutamatergic dysfunction which can further impair the functioning of the hippocampus. Recent studies have shown that N-acetyl cysteine (NAC), a glutamate modulator produces an antidepressant-like effect by normalization of the periterminal release of glutamate and/or antioxidant effects. However, the effects of repeated NAC treatment on depression-induced anxiety, cognitive deficits, and associated neurochemical and structural alterations are relatively unknown. Accordingly, we investigated whether chronic NAC treatment could reverse cognitive deficits, and associated hippocampal volume loss and monoaminergic alterations in the neonatal clomipramine (CLI) model of depression. We found that chronic NAC treatment produces antidepressive and antianhedonic-like effects. NAC treatment also reversed CLI-induced anxiety. Interestingly, repeated NAC treatment improved the performance of CLI rats in rewarded alternation task in T-maze. The antidepressive-like and procognitive effects of NAC was associated with normalization of volume loss in CA1, dentate gyrus (DG) and hilar subfields of the hippocampus. Furthermore, NAC restored CLI-induced decrease in levels of monoamines and normalized enhanced metabolism in the hippocampus. Taken together, chronic NAC treatment ameliorates depressive and anxiety-like behavior, spatial learning deficits, and reverses CLI-induced pathological alterations at structural and neurochemical levels in the hippocampus. Our findings might help in evolving NAC as a viable pharmacotherapy for reversal of cognitive deficits in depression and associated disorders.
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Acetilcisteína/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Depresión/tratamiento farmacológico , Hipocampo/química , Hipocampo/efectos de los fármacos , Acetilcisteína/farmacología , Animales , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Depresión/inducido químicamente , Depresión/metabolismo , Hipocampo/metabolismo , Masculino , Tamaño de los Órganos , Distribución Aleatoria , Ratas , Ratas Wistar , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidadRESUMEN
Human exposure to organomercurials like methylmercury (MeHg) may occur by consumption of contaminated seafood, affecting various vital organs especially, brain contributing to neuro disorders. The citrus flavanone, naringenin (NAR) has shown strong antioxidant and anti-inflammatory effects and therefore may exert cytoprotective effect against xenobiotic agents. Herein, we investigated the neuroprotective role of NAR against MeHg induced functional changes in mitochondria, neuronal cell death and cognitive impairment in a mouse model. A neurotoxic dose of MeHg (4â¯mg/kg.b.wt.) was administered orally to mice for 15 days. This resulted in the reduction of GSH and GST, an increase in mitochondrial DNA damage and memory impairment. On the contrary, NAR pre-treatment (100â¯mg/kg.b.wt.), helped in lowering the oxidative burden which in turn maintained mitochondrial function and prevented induced neuronal cell death, ultimately improving the cognitive impairment. As MeHg intoxication occurs chronically, consumption of the dietary components rich in NAR may have its positive human health impact, ultimately improving the quality of life.
Asunto(s)
Disfunción Cognitiva/prevención & control , Contaminantes Ambientales/toxicidad , Flavanonas/farmacología , Compuestos de Metilmercurio/toxicidad , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Supervivencia Celular/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Modelos Animales de Enfermedad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Reconocimiento Visual de Modelos/efectos de los fármacosRESUMEN
The GRAPES-3 muon telescope located in Ooty, India records rapid (â¼10 min) variations in the muon intensity during major thunderstorms. Out of a total of 184 thunderstorms recorded during the interval of April 2011-December 2014, the one on December 1, 2014 produced a massive potential of 1.3 GV. The electric field measured by four well-separated (up to 6 km) monitors on the ground was used to help estimate some of the properties of this thundercloud, including its altitude and area that were found to be 11.4 km above mean sea level and ≥380 km^{2}, respectively. A charging time of 6 min to reach 1.3 GV implied the delivery of a power of ≥2 GW by this thundercloud that was moving at a speed of â¼60 km h^{-1}. This work possibly provides the first direct evidence for the generation of gigavolt potentials in thunderclouds that could also possibly explain the production of highest-energy (100 MeV) gamma rays in the terrestrial gamma-ray flashes.