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A long proportion of the population is resilient to the negative consequences of stress. Glucocorticoids resulting from endocrine responses to stress are essential adaptive mediators, but also drive alterations to brain function, negatively impacting neuronal connectivity, synaptic plasticity, and memory-related processes. Recent evidence has indicated that organelle function and cellular stress responses are relevant determinant of vulnerability and resistance to environmental stress. At the molecular level, a fundamental mechanism of cellular stress adaptation is the maintenance of proteostasis, which also have key roles in sustaining basal neuronal function. Here, we discuss recent evidence suggesting that proteostasis unbalance at the level of the endoplasmic reticulum, the main site for protein folding in the cell, represents a possible mechanistic link between individuals and cellular stress.

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Stressors elicit a neuroendocrine response leading to increased levels of glucocorticoids, allowing the organism to adapt to environmental changes and maintain homeostasis. Glucocorticoids have a broad effect in the body, modifying the activity of the immune system, metabolism, and behavior through the activation of receptors in the limbic system. Chronic exposition to stressors operates as a risk factor for psychiatric diseases such as depression and posttraumatic stress disorder. Among the cellular alterations observed as a consequence of environmental stress, alterations to organelle function at the level of mitochondria and endoplasmic reticulum (ER) are emerging as possible factors contributing to neuronal dysfunction. ER proteostasis alterations elicit the unfolded protein response (UPR), a conserved signaling network that re-establish protein homeostasis. In addition, in the context of brain function, the UPR has been associated to neurodevelopment, synaptic plasticity and neuronal connectivity. Recent studies suggest a role of the UPR in the adaptive behavior to stress, suggesting a mechanistic link between environmental and cellular stress. Here, we revise recent evidence supporting an evolutionary connection between the neuroendocrine system and the UPR to modulate behavioral adaptive responses.

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BACKGROUND: The degeneration of the pedunculopontine nucleus (PPN) precedes the degeneration of the nigral cells in the pre-symptomatic stages of Parkinson's disease (PD). Although the literature recognizes that a lesion of the PPN increases the vulnerability of dopaminergic cells, it is unknown if this risk is associated with the loss of capability of handling the dopaminergic function. METHODS: In this paper, the effects of a unilateral neurotoxic lesion of the PPN in tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) mRNA expression in nigrostriatal tissue were evaluated. Three experimental groups were organized: non-treated rats, NMDA-lesioned rats and Sham-operated rats. RESULTS: Seven days after the PPN lesion, in nigral tissue, TH mRNA expression was higher in comparison with control groups (p < 0.05); in contrast, VMAT2 mRNA expression showed a significant decrease (p < 0.01). DAT mRNA expression showed a significant decrease (p < 0.001) in the striatal tissue. Comparing nigral neuronal density of injured and control rats revealed no significant difference seven days post-PPN injury. CONCLUSIONS: Findings suggest that the PPN lesion modifies the mRNA expression of the proteins associated with dopaminergic homeostasis at nigrostriatal level. It could represent vulnerability signals for nigral dopaminergic cells and further increase the risk of degeneration of these cells.

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Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1ß and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-κB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1ß and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-κB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non-neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-κB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation.

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La enfermedad de Parkinson es una enfermedad neurodegenerativa crónica que afecta a las personas de la tercera edad. En una minoría de los casos la enfermedad es de origen genético pero en el resto, la causa es idiopática. En este sentido, la acumulación de los radicales libres y la pérdida de la homeostasis del glutatión se han señalado como posibles agentes causales. El presente texto se propuso revisar las evidencias experimentales que apoyan la participación de los radicales libres y la pérdida de la homeostasis del glutatión en el comienzo y la progresión de la degeneración de la substantianigrapars compacta. El estrés oxidativo en la enfermedad de Parkinson´s puede estar relacionado con las propiedades pro-oxidantes intrínsecas de la dopamina y elevadas concentraciones de hierro en la substantianigrapars compacta, que promueven la oxidación de la dopamina y la generación de especies reactivas del oxígeno. Cualquier evento que desencadene estos mecanismos, genera un daño celular. La disminución del glutatión es una de las alteraciones bioquímicas más tempranas, detectadas en asociación con la enfermedad de Parkinson y se ha relacionado con la inhibición del complejo I de la cadena de transporte mitocondrial, daño oxidativo, activación glial, entre otros que favorecen la neurodegeneración. Estas evidencias sugieren la necesidad de mantener la homeostasis del glutatión en el sistema dopaminérgico y su vínculo con la etiología de la degeneración nigro-estriatal, lo que tiene una potencial aplicación en la práctica clínica.

Parkinson's disease is a chronic neurodegenerative condition affecting elderly persons. In a minority of cases the disease has a genetic origin, but in most the cause is idiopathic. Accumulation of free radicals and loss of glutathione homeostasis have been pointed at as possible causal agents. The purpose of the study was to review experimental evidence supporting the involvement of free radicals and loss of glutathione homeostasis in the outset and progress of substantia nigra pars compacta degeneration. Oxidative stress in Parkinson's disease may be related to the intrinsic pro-oxidant properties of dopamine and high iron concentrations in the substantia nigra pars compacta, promoting dopamine oxidation and the generation of reactive oxygen species. Any event triggering these mechanisms will cause cell damage. Glutathione reduction is one of the earliest biochemical alterations detected in association with Parkinson's disease, and it has been related to the inhibition of complex I of the mitochondrial transport chain, oxidative damage and glial activation, among other factors leading to neurodegeneration. This evidence points to the need to maintain glutathione homeostasis in the dopaminergic system, as well as its relationship to the etiology of nigrostriatal degeneration, of potential application in clinical practice.

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La enfermedad de Parkinson es una enfermedad neurodegenerativa crónica que afecta a las personas de la tercera edad. En una minoría de los casos la enfermedad es de origen genético pero en el resto, la causa es idiopática. En este sentido, la acumulación de los radicales libres y la pérdida de la homeostasis del glutatión se han señalado como posibles agentes causales. El presente texto se propuso revisar las evidencias experimentales que apoyan la participación de los radicales libres y la pérdida de la homeostasis del glutatión en el comienzo y la progresión de la degeneración de la substantianigrapars compacta. El estrés oxidativo en la enfermedad de Parkinson´s puede estar relacionado con las propiedades pro-oxidantes intrínsecas de la dopamina y elevadas concentraciones de hierro en la substantianigrapars compacta, que promueven la oxidación de la dopamina y la generación de especies reactivas del oxígeno. Cualquier evento que desencadene estos mecanismos, genera un daño celular. La disminución del glutatión es una de las alteraciones bioquímicas más tempranas, detectadas en asociación con la enfermedad de Parkinson y se ha relacionado con la inhibición del complejo I de la cadena de transporte mitocondrial, daño oxidativo, activación glial, entre otros que favorecen la neurodegeneración. Estas evidencias sugieren la necesidad de mantener la homeostasis del glutatión en el sistema dopaminérgico y su vínculo con la etiología de la degeneración nigro-estriatal, lo que tiene una potencial aplicación en la práctica clínica(AU)

Parkinsons disease is a chronic neurodegenerative condition affecting elderly persons. In a minority of cases the disease has a genetic origin, but in most the cause is idiopathic. Accumulation of free radicals and loss of glutathione homeostasis have been pointed at as possible causal agents. The purpose of the study was to review experimental evidence supporting the involvement of free radicals and loss of glutathione homeostasis in the outset and progress of substantia nigra pars compacta degeneration. Oxidative stress in Parkinsons disease may be related to the intrinsic pro-oxidant properties of dopamine and high iron concentrations in the substantia nigra pars compacta, promoting dopamine oxidation and the generation of reactive oxygen species. Any event triggering these mechanisms will cause cell damage. Glutathione reduction is one of the earliest biochemical alterations detected in association with Parkinsons disease, and it has been related to the inhibition of complex I of the mitochondrial transport chain, oxidative damage and glial activation, among other factors leading to neurodegeneration. This evidence points to the need to maintain glutathione homeostasis in the dopaminergic system, as well as its relationship to the etiology of nigrostriatal degeneration, of potential application in clinical practice(AU)

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