Trauma-like exposure alters neuronal apoptosis, Bin1, Fkbp5 and NR2B expression in an amyloid-beta (1-42) rat model of Alzheimer's disease.

Post-traumatic stress disorder (PTSD) is a risk factor in the development and progression of Alzheimer's disease (AD), with unclear underlying mechanisms. Recently, we provided data showing the effect of trauma-like stress on Bin1 and Fkbp5 expression in the prefrontal cortex of Aß(1-42) lesioned animals. This present work sought to expand the study by examining the involvement of the amygdala and hippocampus, in addition to highlighting the role of NR2B in the co-occurrence of trauma-like stress and an Aß AD-like pathology. Trauma-like condition was induced by exposing the animals to footshocks. Aß(1-42) was injected into the hippocampus of the animals to induce AD-like pathology. Cognitive functions were assessed in the Morris water maze (MWM) and novel object recognition tests, after which amygdala and hippocampus tissues were harvested for neurochemical analyses. We found that the combination of footshocks and Aß(1-42) lesion caused a decrease in the number of crossings in the target quadrant of the Morris water maze test, indicating memory deficits. Footshocks caused a further downregulation of Bin1 in the amygdala of Aß(1-42)-lesioned rats. Prior exposure to footshocks downregulated NR2B in the hippocampus of Aß(1-42)-lesioned rats. In addition, a combination of footshocks and Aß(1-42) lesion sustained the upregulation of Fkbp5 in the hippocampus and amygdala. A combination of footshocks and Aß(1-42) lesion increased neuronal apoptosis in the hippocampus and amygdala. In conclusion, exposure to a trauma-like condition may influence AD-like pathology, leading to exaggerated behavioural and molecular changes in the amygdala and hippocampus.

Inescapable footshocks induce molecular changes in the prefrontal cortex of rats in an amyloid-beta-42 model of Alzheimer's disease.

Alzheimer's disease (AD) affects several brain areas, including the prefrontal cortex (PFC) involved in execution, working memory, and fear extinction. Despite these critical roles, the PFC is understudied in AD pathology. People with post-traumatic stress disorder (PTSD) have twice the risk of developing AD, and the underlying mechanisms linking these two diseases are less understood. Here, we investigated the effect of footshock stress on behavioural vis-a-vis molecular changes in the PFC of an amyloid-beta (Aß)-42 lesion rat model of AD. Trauma-like conditions were induced by exposing the animals to several footshocks. AD-like condition was induced via intra-hippocampal injection of Aß-42 peptide. Following Aß-42 injections, animals were tested for behavioural changes using the Open Field Test (OFT) and Y-maze test. The PFC was later harvested for neurochemical analyses. Our results showed an interactive effect of footshocks and Aß-42 lesion on: reduced percentage alternation in the Y-maze test, suggesting memory impairment; reduced number of line crosses and time spent in the centre square of the OFT, indicating anxiogenic responses. Similarly, there was an interactive effect of footshocks and Aß-42 lesion on: increased FK506 binding protein 51 (FKBP5) expression, which can be associated with stress-induced anxiogenic behaviours; and increased neuronal apoptosis in the PFC of the animals. In addition, footshocks, as well as Aß-42 lesion, reduced superoxide dismutase levels and Bridging Integrator-1 (BIN1) expression in the PFC of the animals, which can be linked to the observed memory impairment. In conclusion, our findings indicate that footshocks exaggerate PFC-associated behavioural and molecular changes induced by an AD-like pathology.

Exposure to footshock stress downregulates antioxidant genes and increases neuronal apoptosis in an Aß(1-42) rat model of Alzheimer's disease.

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that develops from exposure to trauma, mostly when normal psychological mechanisms fail. Studies have shown that people who have PTSD are susceptible to developing dementia, mostly Alzheimer's disease (AD), suggesting common underlying risk factors in the comorbidity. However, data elucidating links between these conditions is scarce. Here we show that footshock stress exacerbates AD-like pathology. To induce a trauma-like condition, the rats were exposed to multiple intense footshocks followed by a single reminder. This was followed by bilateral intrahippocampal lesions with amyloid-beta (Aß) (1-42), to model AD-like pathology. We found that footshocks increased anxiety behavior and impaired fear memory extinction in Aß(1-42) lesioned rats. We also found a reduced expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD (P) H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and an increased expression of Kelch-like ECH-associated protein 1 (Keap1) in the amygdala and hippocampus. Furthermore, oxidative stress level was sustained, which was associated with increased apoptosis in the amygdala and hippocampus. Our finding suggests that AD-like pathology can induce oxidative changes in the amygdala and hippocampus, which can be exaggerated by footshock stress.

Long-Term Treatment with Fluvoxamine Decreases Nonmotor Symptoms and Dopamine Depletion in a Postnatal Stress Rat Model of Parkinson's Disease.

Nonmotor symptoms (NMS) such as anxiety, depression, and cognitive deficits are frequently observed in Parkinson's disease (PD) and precede the onset of motor symptoms by years. We have recently explored the short-term effects of Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) on dopaminergic neurons in a parkinsonian rat model. Here, we report the long-term effects of Fluvoxamine, on early-life stress-induced changes in the brain and behavior. We specifically evaluated the effects of Fluvoxamine on brain mechanisms that contribute to NMS associated with PD in a unilateral 6-hydroxydopamine-lesioned rat model. A 14-day early postnatal maternal separation protocol was applied to model early-life stress followed by unilateral intracerebral infusion of 6-hydroxydopamine (6-OHDA) to model aspects of parkinsonism in rats. The anxiolytic, antidepressant, and cognitive effects of Fluvoxamine were confirmed using the elevated plus-maze (EPM) test, sucrose preference test (SPT), and Morris water maze (MWM) test. Further to that, our results showed that animals exposed to early-life stress displayed increased plasma corticosterone and malondialdehyde (MDA) levels which were attenuated by Fluvoxamine treatment. A 6-OHDA lesion effect was evidenced by impairment in the limb-use asymmetry test as well as decreased dopamine (DA) and serotonin levels in the striatum, prefrontal cortex, and hippocampus. These effects were surprisingly attenuated by Fluvoxamine treatment in all treated rats. This study is the first to suggest that early and long-term treatment of neuropsychological diseases with Fluvoxamine may decrease the vulnerability of dopaminergic neurons that degenerate in the course of PD.

Dielectric Constant and Conductivity of Blood Plasma: Possible Novel Biomarkers for Alzheimer's Disease.

Alzheimer's disease is a complex debilitating neurodegenerative disease for which there is no cure. The lack of reliable biomarkers for Alzheimer's disease has made the evaluation of the efficacy of new treatments difficult and reliant on only clinical symptoms. In an aged population where cognitive function may be deteriorating for other reasons, the dependence on clinical symptoms is also unreliable. However, it is well established that infusion of ß-amyloid into the dorsal hippocampus of rats leads to cognitive impairment in a rat model of Alzheimer's disease. Moreover, the blood plasma of ß-amyloid-lesioned rats exhibits a distinct variation of the dielectric constant and conductivity when compared to that of normal rats in a time-dependent manner. These two electric parameters of blood plasma may therefore act as potential biomarkers for dementia due to Alzheimer's disease. This review is aimed at highlighting evidences that support blood plasma electrical properties, e.g., dielectric constant and conductivity as possible novel biomarkers for the early development and progression of dementia due to Alzheimer's disease.

Memory decline correlates with increased plasma cytokines in amyloid-beta (1-42) rat model of Alzheimer's disease.

Dysregulation of inflammatory markers like cytokines is implicated in the pathophysiology of Alzheimer's disease (AD). Altered level of these cytokines show that pathogenesis of AD is beyond dysfunction of neurons resulting from amyloid beta accumulation but involves neuroinflammatory mechanisms elicited by the neuroimmune cell. In this study, we investigated the effect of amyloid-beta (1-42) (Aß(1-42)) on memory and how inflammatory markers respond to this model of AD. Male Sprague-Dawley rats were used for this study. The animals were randomly divided into four groups euthanized on day 3, 7, 10 and 14 post-lesion with amyloid-beta (5 µg/5 µl) while corresponding control groups were stereotaxically injected with a vehicle (5 µl of 0.01 M phosphate- buffered saline). The Morris water maze (MWM) test to access learning and memory was conducted pre and post-lesion and blood was collected through cardiac puncture on day 3, 7, 10 and 14 post lesion. Multiplex immunoassay was performed to determine the plasma levels of IL-1ß, IL-6, IL-10 and TNF-α. Our results showed impaired spatial memory and elevated plasma levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) with a concomitantly lowered level of the anti-inflammatory cytokine (IL-10) in the Aß(1-42) lesioned rats when compared to the vehicle groups. This study showed a negative correlation between the decline in performance of the spatial memory task and plasma levels of the pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α and positive correlation with the anti-inflammatory cytokine IL-10. In conclusion, this study most importantly demonstrated an association between progressive decline in spatial memory and increased plasma cytokine level induced by the infusion of Aß(1-42).

Early Life Stress, Depression And Parkinson's Disease: A New Approach.

This review aims to shed light on the relationship that involves exposure to early life stress, depression and Parkinson's disease (PD). A systematic literature search was conducted in Pubmed, MEDLINE, EBSCOHost and Google Scholar and relevant data were submitted to a meta-analysis . Early life stress may contribute to the development of depression and patients with depression are at risk of developing PD later in life. Depression is a common non-motor symptom preceding motor symptoms in PD. Stimulation of regions contiguous to the substantia nigra as well as dopamine (DA) agonists have been shown to be able to attenuate depression. Therefore, since PD causes depletion of dopaminergic neurons in the substantia nigra, depression, rather than being just a simple mood disorder, may be part of the pathophysiological process that leads to PD. It is plausible that the mesocortical and mesolimbic dopaminergic pathways that mediate mood, emotion, and/or cognitive function may also play a key role in depression associated with PD. Here, we propose that a medication designed to address a deficiency in serotonin is more likely to influence motor symptoms of PD associated with depression. This review highlights the effects of an antidepressant, Fluvoxamine maleate, in an animal model that combines depressive-like symptoms and Parkinsonism.

Fluvoxamine maleate effects on dopamine signaling in the prefrontal cortex of stressed Parkinsonian rats: Implications for learning and memory.

Parkinson's disease (PD) is also associated with cognitive impairment and reduced extrinsic supply of dopamine (DA) to the prefrontal cortex (PFC). In the present study, we looked at whether exposure to early life stress reduces DA and serotonin (5-HT) concentration in the PFC thus leading to enhanced cognitive impairment in a Parkinsonian rat model. Maternal separation was the stressor used to develop an animal model for early life stress that has chronic effects on brain and behavior. Sprague-Dawley rats were treated with the antidepressant Fluvoxamine maleate (FM) prior to a unilateral 6-hydroxydopamine (6-OHDA) lesion to model motor deficits in rats. The Morris water maze (MWM) and the forelimb use asymmetry (cylinder) tests were used to assess learning and memory impairment and motor deficits respectively. Blood plasma was used to measure corticosterone concentration and prefrontal tissue was collected for lipid peroxidation, DA, and 5-HT analysis. Our results show that animals exposed to early life stress displayed learning and memory impairment as well as elevated basal plasma corticosterone concentration which were attenuated by treatment with FM. A 6-OHDA lesion effect was evidenced by impairment in the cylinder test as well as decreased DA and 5-HT concentration in the PFC. These effects were attenuated by FM treatment resulting in higher DA concentration in the PFC of treated animals than in non-treated animals. This study suggests that DA and 5-HT signaling in the PFC are responsive to FM and may reduce stress-induced cognitive impairment in PD.

Fluvoxamine maleate normalizes striatal neuronal inflammatory cytokine activity in a Parkinsonian rat model associated with depression.

Cytokine dysfunction is associated with both depression and Parkinson's disease (PD) pathophysiology. Inflammatory cytokines in neural and behavioral processes are involved in the production and/or maintenance of depression in PD. In this study we looked at how Fluvoxamine treatment regulates depressive-like signs, motor impairments and the expression of IL-1ß, IL-6, TNF-α, TGF-ß and IL-10 cytokines in the striatum of a stressed Parkinsonian rat model. Early maternal separation was used to model stress and depressive-like signs in rats. Maternally separated adult rats were treated with Fluvoxamine for 30days prior to 6-hydroxydopamine (6-OHDA) lesion. The sucrose preference test (SPT) and the limb-use asymmetry test (cylinder test) were used to evaluate anhedonia and motor impairments respectively. Lipid peroxidation and cytokine expression were measured in striatal tissue using ELISA and real-time PCR techniques respectively. Our results show that maternal separation resulted in anhedonia and exacerbated 6-OHDA lesion but Fluvoxamine treatment attenuated these effects. Lipid peroxidation, mRNA levels of IL-1ß, IL-6 and TNF-α were down-regulated while IL-10 and TGF-ß levels were up-regulated in the lesioned striatum of Fluvoxamine treated rats. This study shows that early treatment with Fluvoxamine may attenuate inflammation on injured striatal neurons by favoring anti-inflammatory cytokine expression while decreasing pro-inflammatory cytokine release in the brain. This suggests a role of Fluvoxamine as a potential therapeutic intervention targeting neuronal inflammation associated with PD.

Anti-parkinsonian effects of fluvoxamine maleate in maternally separated rats.

Exposure to early life stress has been shown to result in anxiety-like symptoms and exacerbates degeneration of dopaminergic neurons in a rat model of Parkinson's disease (PD). First line treatment for anxiety disorders includes the use of Fluvoxamine maleate (FM). In this study, we investigated whether treating anxiety-like symptoms with FM has an effect in alleviating the neurotoxic effects of 6-OHDA in a parkinsonian rat model. Early maternal separation was used to create a rat model that depicts anxiety-like symptoms. Maternally separated adult Sprague-Dawley rats were treated with FM prior to and following lesion with 6-hydroxydopamine (6-OHDA). The elevated plus-maze (EPM) and the forelimb akinesia tests were used to evaluate anxiety-like symptoms and motor impairment respectively. Blood plasma was used to measure corticosterone concentration, and striatal tissue was collected for dopamine (DA) and serotonin (5-HT) analysis. Our results show that animals exposed to early life stress displayed increased anxiety-like symptoms and elevated basal plasma corticosterone concentration which were attenuated by treatment with FM. A 6-OHDA lesion effect was evidenced by impairment in the forelimb akinesia test as well as decreased DA and 5-HT concentrations in the lesioned striatum. These effects were attenuated on DA neurons by FM treatment in the pre-lesion treated as opposed to the post-lesion treated rats. This study suggests that early treatment of anxiety-like behavior decreases the vulnerability of DA neurons to neurotoxic insults later in life thus slowing down DA degeneration in PD.