Alzheimer's disease (AD) is the most common form of dementia worldwide. β-amyloid peptide (Aβ) is currently assumed to be the main cause of synaptic dysfunction and cognitive impairments in AD, but ...the molecular signaling pathways underlying its neurotoxic consequences have not yet been completely explored. Additional investigations regarding these pathways will contribute to development of new therapeutic targets. In context, developing evidence suggest that Aβ decreases brain-derived neurotrophic factor (BDNF) mostly by lowering phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) protein. In fact, it has been observed that brain or serum levels of BDNF appear to be beneficial markers for cognitive condition. In addition, the participation of transcription mediated by CREB has been widely analyzed in the memory process and AD development. Designing pharmacologic or genetic therapeutic approaches based on the targeting of CREB-BDNF signaling could be a promising treatment potential for AD. In this review, we summarize data demonstrating the role of CREB-BDNF signaling pathway in cognitive status and mediation of Aβ toxicity in AD. Finally, we also focus on the developing intervention methods for improvement of cognitive decline in AD based on targeting of CREB-BDNF pathway.
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•BDNF and CREB are key downstream mediators of Aβ toxicity•BDNF level is correlated with cognitive status•Aβ decreases BDNF primarily by reducing phosphorylated CREB protein
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD ...pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta (Aβ) aggregation and deposition are critical pathogenic processes in AD, leading to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptic degeneration, and dementia. In LOAD, the causes of Aβ accumulation and neuronal loss are not completely clear. Importantly, the blood-brain barrier (BBB) disruption seems to present an essential role in the induction of neuroinflammation and consequent AD development. In addition, we propose that the systemic inflammation triggered by conditions like metabolic diseases or infections are causative factors of BBB disruption, coexistent inflammatory cascade and, ultimately, the neurodegeneration observed in AD. In this regard, the use of anti-inflammatory molecules could be an interesting strategy to treat, delay or even halt AD onset and progression. Herein, we review the inflammatory cascade and underlying mechanisms involved in AD pathogenesis and revise the anti-inflammatory effects of compounds as emerging therapeutic drugs against AD.
Abstract Reactive oxygen species (ROS) have been shown to play a role in the pathophysiology of depression. Taking into account that experimental chronic unpredictable stress (CUS) induces ...depressive-like behavior and that ascorbic acid has antidepressant-like effect in animals, the objective of this study was to investigate the influence of ascorbic acid on depressive-like behavior induced by CUS paradigm, serum corticosterone levels and markers of oxidative stress in cerebral cortex and hippocampus of mice. Animals were submitted to CUS procedure during 14 days. From the 8th to the 14th day mice received ascorbic acid (10 mg/kg) or fluoxetine (10 mg/kg, conventional antidepressant, positive control) once a day by oral route. On 15th day behavioral and biochemical parameters were analyzed. CUS exposure caused a depressive-like behavior evidenced by the increased immobility time in the tail suspension test and decreased time in which mice spent grooming in the splash test. Depressive-like behavior induced by CUS was accompanied by a significant increased lipid peroxidation (cerebral cortex and hippocampus), decreased catalase (CAT) (cerebral cortex and hippocampus) and glutathione reductase (GR) (hippocampus) activities and reduced levels of glutathione (cerebral cortex). Repeated ascorbic acid or fluoxetine administration significantly reversed CUS-induced depressive-like behavior and oxidative damage. No alteration was observed in locomotor activity, corticosterone levels and glutathione peroxidase (GPx) activity. These findings indicate a rapid and robust effect of ascorbic acid in reversing behavioral and biochemical alterations induced by CUS in mice, suggesting that this vitamin may be an alternative approach for the management of depressive symptoms.
The oxidative stress, a relevant pathway in the development of mood disorders, is the result of imbalance between the production of reactive species (RS) and the organism's ability to inhibit or ...repair the damage caused by them through its endogenous antioxidant defenses or the use of exogenous antioxidants (Halliwell, 2011). In the paper “Acupuncture relieves stress-induced depressive behavior by reducing oxidative stress and neuroapoptosis in rats,” the authors demonstrated that acupuncture present antidepressant-like effects by reducing oxidative stress products via regulating the nuclear transcription factor erythroid-2-like factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and, consequently, prevented neuronal apoptosis in the chronic unpredictable mild stress (CUMS) model (Cheng et al.). While a causal relationship between gene expression changes and behavioral resilience to stress was not established here, the results support the idea that the state of the glutamatergic/GABAergic circuits in the prefrontal cortex before exposure to chronic unpredictable mild stress might directly contribute to resilience to stress-related mood disorders. ...studying sex differences in ketamine effects on those circuits might help our understanding of the mechanisms underlying increased vulnerability to emotional deregulations in females.
Major depressive disorder (MDD) is one of the most prevalent and life-threatening forms of mental illnesses affecting elderly people and has been associated with poor cognitive function. Recent ...evidence suggests a strong relationship between MDD and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), as well as natural processes of aging. Changes in the neuroplasticity, morphology, and neurotransmission in the brain are seem to be associated to both, MDD and neurodegenerative diseases. In addition, there is evidence that psychological stress and MDD are associated with molecular and cellular signs of accelerated aging. This review will highlight the relationship between MDD, the aging process, and neurodegenerative diseases, emphasizing the neurochemical processes involved.
Major depressive disorder (MDD) and Neurodegenerative Diseases pathophysiologic interactions. Patients with MDD have a susceptibility to acquiring Huntington's disease, Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and Parkinson's Disease (PD); in patients with neurodegenerative diseases there is a higher prevalence of MDD. Elderly individuals with MDD have altered monoamine levels, Hypothalamic-Pituitary-Adrenal (HPA) axis dysfunctions, decreased brain neurotrophic-derived factor (BDNF) levels, morphologic alterations in the brain, and neuroinflammation. MDD and HD both present with changes in the serotoninergic system, primarily serotonin (5-HT) and the 5-HT1A receptor; in addition, brain morphologic changes and decreased neurogenesis are found. AD and MDD share alterations in proteins involved with neural plasticity, such as BDNF and glycogen synthase kinase-3β (GSK-3β). Alterations in amyloid β are also common. Zinc levels, brain morphology changes and neuroinflammation are also shared between AD and MDD. Monoamine alterations are demonstrated in both ALS and MDD. PD and MDD also share altered monoamines, in addition to glutamate and BDNF level changes. Display omitted
Although numerous studies have investigated the mechanisms underlying the fast and sustained antidepressant-like effects of ketamine, the contribution of the glucocorticoid receptor (GR) and ...dendritic branching remodeling to its responses remain to be fully established. This study investigated the ability of a single administration of ketamine to modulate the GR and dendritic branching remodeling and complexity in the hippocampus of mice subjected to chronic corticosterone (CORT) administration. CORT was administered for 21 days, followed by a single administration of ketamine (1 mg ∕kg, i.p.) or fluoxetine (10 mg ∕kg, p.o., conventional antidepressant) in mice. On 22
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, 24 h after the treatments, GR immunocontent in the hippocampus was analyzed by western blotting, while the dendritic arborization and dendrite length in the ventral and dorsal dentate gyrus (DG) of the hippocampus was analyzed by Sholl analysis. Chronic CORT administration downregulated hippocampal GR immunocontent, but this alteration was completely reversed by a single administration of ketamine, but not fluoxetine. Moreover, CORT administration significantly decreased dendritic branching in the dorsal and ventral DG areas and caused a mild decrease in dendrite length in both regions. Ketamine, but not fluoxetine, reversed CORT-induced dendritic branching loss in the ventral and dorsal DG areas, regions associated with mood regulation and cognitive functions, respectively. This study provides novel evidence that a single administration of ketamine, but not fluoxetine, rescued the impairments on GR and dendritic branching in the hippocampus of mice subjected to chronic CORT administration, effects that may be associated with its rapid antidepressant response.
Critical illness encompasses a wide spectrum of life-threatening clinical conditions requiring intensive care. Our objective was to evaluate cognitive, inflammatory and cellular metabolism ...alterations in the central nervous system in an animal model of critical illness induced by zymosan. For this Wistar rats that were divided into Sham and zymosan. Zymozan was administered once intraperitoneally (30 g/100 g body weight) diluted in mineral oil. The animals were submitted to behavioral tests of octagonal maze, inhibitory avoidance and elevated plus maze. Brain structures (cortex, prefrontal and hippocampus) were removed at 24 h, 4, 7 and 15 days after zymosan administration for analysis of cytokine levels (TNF-α, IL-1b, IL-6 and IL-10), oxidative damage and oxygen consumption. Zymosan-treated animals presented mild cognitive impairment both in aversive (inhibitory avoidance) and non-aversive (octagonal maze) tasks by day 15. However, they did not show increase in anxiety (elevated-plus maze). The first neurochemical alteration found was an increase in brain pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) at day 4th in the hippocampus. In cortex, a late (7 and 15 days) increase in TNF-α was also noted, while the anti-inflammatory cytokine IL-10 decrease from 4 to 15 days. Oxygen consumption was decreased in the hippocampus and pre-frontal, but not cortex, only at 7 days. Additionally, it was observed a late (15 days) increase in oxidative damage parameters. This characterization of brain dysfunction in rodent model of critical illness reproduces some of the alterations reported in humans such neuropsychiatric disorders, especially depression, memory loss and cognitive changes and can add to the nowadays used models.
Studies have demonstrated an association between stressful conditions and the onset of clinical depression. Considering the antidepressant-like properties of ascorbic acid in both experimental and ...clinical approaches, we evaluated the beneficial effect of this vitamin on restraint stress-induced behavioral and neurochemical alterations. Acute restraint stress caused a depressive-like behavior in the forced swimming test, accompanied by increased lipid peroxidation (cerebral cortex and hippocampus); increased superoxide dismutase (cerebral cortex and hippocampus), glutathione reductase (cerebral cortex), and glutathione peroxidase (cerebral cortex and hippocampus) activities; and elevated expression of Bcl-2 (hippocampus). Oral administration of ascorbic acid (1 mg/kg) or fluoxetine (10 mg/kg) 1 h before restraint stress prevented the stress-induced increase on immobility time in the forced swimming test. Moreover, this vitamin reduced lipid peroxidation to control levels and restored the activity of superoxide dismutase, glutathione reductase, and glutathione peroxidase. Ascorbic acid had no effect on the increased level of Bcl-2 induced by stress. Glutathione levels, glycogen synthase kinase-3β phosphorylation, and Bax expression were not altered by stress or ascorbic acid administration. Besides reinforcing the antioxidant potential of ascorbic acid, our results support the notion that oxidative stress plays a role in the pathogenesis and treatment of stress-induced depression.
Mood disorders are a leading cause of morbidity and mortality, yet their underlying pathophysiology remains unclear. Animal models serve as a powerful tool for investigating the neurobiological ...mechanisms underlying psychiatric disorders; however, no animal model developed to date can fully mimic the "corresponding" human psychiatric disorder. In this scenario, the development of different animal models contributes to our understanding of the neurobiology of these disorders and provides the possibility of preclinical pharmacologic screening. The present review seeks to provide a comprehensive overview of traditional and recent animal models, recapitulating different features and the possible pathologic mechanisms of mood disorders emulated by these models.
The present study aimed to evaluate the effect of folic acid treatment in an animal model of aging induced by D-galactose (D-gal). For this propose, adult male Wistar rats received D-gal ...intraperitoneally (100 mg/kg) and/or folic acid orally (5 mg/kg, 10 mg/kg or 50 mg/kg) for 8 weeks. D-gal caused habituation memory impairment, and folic acid (10 mg/kg and 50 mg/kg) reversed this effect. However, folic acid 50 mg/kg per se caused habituation memory impairment. D-gal increased the lipid peroxidation and oxidative damage to proteins in the prefrontal cortex and hippocampus from rats. Folic acid (5 mg/kg, 10 mg/kg, or 50 mg/kg) partially reversed the oxidative damage to lipids in the hippocampus, but not in the prefrontal cortex, and reversed protein oxidative damage in the prefrontal cortex and hippocampus. D-gal induced synaptophysin and BCL-2 decrease in the hippocampus and phosphorylated tau increase in the prefrontal cortex. Folic acid was able to reverse these D-gal-related alterations in the protein content. The present study shows folic acid supplementation as an alternative during the aging to prevent cognitive impairment and brain alterations that can cause neurodegenerative diseases. However, additional studies are necessary to elucidate the effect of folic acid in aging.
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