Molecular Mechanisms Linking Osteoarthritis and Alzheimer's Disease: Shared Pathways, Mechanisms and Breakthrough Prospects.

Alzheimer's disease (AD) is a progressive neurodegenerative disease mostly affecting the elderly population. It is characterized by cognitive decline that occurs due to impaired neurotransmission and neuronal death. Even though deposition of amyloid beta (Aß) peptides and aggregation of hyperphosphorylated TAU have been established as major pathological hallmarks of the disease, other factors such as the interaction of genetic and environmental factors are believed to contribute to the development and progression of AD. In general, patients initially present mild forgetfulness and difficulty in forming new memories. As it progresses, there are significant impairments in problem solving, social interaction, speech and overall cognitive function of the affected individual. Osteoarthritis (OA) is the most recurrent form of arthritis and widely acknowledged as a whole-joint disease, distinguished by progressive degeneration and erosion of joint cartilage accompanying synovitis and subchondral bone changes that can prompt peripheral inflammatory responses. Also predominantly affecting the elderly, OA frequently embroils weight-bearing joints such as the knees, spine and hips leading to pains, stiffness and diminished joint mobility, which in turn significantly impacts the patient's standard of life. Both infirmities can co-occur in older adults as a result of independent factors, as multiple health conditions are common in old age. Additionally, risk factors such as genetics, lifestyle changes, age and chronic inflammation may contribute to both conditions in some individuals. Besides localized peripheral low-grade inflammation, it is notable that low-grade systemic inflammation prompted by OA can play a role in AD pathogenesis. Studies have explored relationships between systemic inflammatory-associated diseases like obesity, hypertension, dyslipidemia, diabetes mellitus and AD. Given that AD is the most common form of dementia and shares similar risk factors with OA-both being age-related and low-grade inflammatory-associated diseases, OA may indeed serve as a risk factor for AD. This work aims to review literature on molecular mechanisms linking OA and AD pathologies, and explore potential connections between these conditions alongside future prospects and innovative treatments.

Evaluation of New Potential Inflammatory Markers in Patients with Nonvalvular Atrial Fibrillation.

Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its maintenance. We aimed to evaluate a range of inflammatory markers as potentially involved in the pathophysiology of individuals with nonvalvular AF (NVAF). A total of 105 subjects were enrolled and divided into two groups: patients with NVAF (n = 55, mean age 72 ± 8 years) and a control group of individuals in sinus rhythm (n = 50, mean age 71 ± 8 years). Inflammatory-related mediators were quantified in plasma samples by using Cytometric Bead Array and Multiplex immunoassay. Subjects with NVAF presented significantly elevated values of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon-gamma, growth differentiation factor-15, myeloperoxidase, as well as IL-4, interferon-gamma-induced protein (IP-10), monokine induced by interferon-gamma, neutrophil gelatinase-associated lipocalin, and serum amyloid A in comparison with controls. However, after multivariate regression analysis adjusting for confounding factors, only IL-6, IL-10, TNF, and IP-10 remained significantly associated with AF. We provided a basis for the study of inflammatory markers whose association with AF has not been addressed before, such as IP-10, in addition to supporting evidence about molecules that had previously been associated with the disease. We expect to contribute to the discovery of markers that can be implemented in clinical practice hereafter.

Evaluation of serum haptoglobin levels and Hp1-Hp2 polymorphism in the haptoglobin gene in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is an arrhythmia that involves structural and electrophysiological abnormalities. Many of the AF-related clinical conditions are associated with an increase in inflammatory and oxidative factors. Haptoglobin (Hp) is an acute phase protein whose biological role is to promote clearance of free hemoglobin (Hb). In addition, for being considered an inflammatory marker, Hp represents a protective mechanism against the oxidative effects of Hb. The Hp1-Hp2 polymorphism at Hp locus can lead to three phenotypes related to structural and functional differences in the protein. The objective of this study were to evaluate Hp levels and Hp1-Hp2 polymorphism at Hp locus in patients with AF compared to a control group. METHODS AND RESULTS: This study included 65 patients with AF and 54 individuals without the arrhythmia. Biochemical parameters were determined using Vitros system, plasma levels of Hp were measured in serum samples by using ELISA method and polymorphisms were verified by PCR technique. Plasma Hp levels, as well as allelic and genotypic frequency, were not associated with AF. The levels of Hp also did not differ among the genotypes according to the applied models. CONCLUSIONS: The results suggest that Hp levels and Hp1-Hp2 polymorphism are not associated to AF.

Cannabidiol prevents lipopolysaccharide-induced sickness behavior and alters cytokine and neurotrophic factor levels in the brain.

BACKGROUND: Major depressive disorder (MDD) affects millions of people worldwide. While the exact pathogenesis is yet to be elucidated, the role of neuro-immune signaling has recently emerged. Despite major advances in pharmacotherapy, antidepressant use is marred by limited efficacy and potential side effects. Cannabidiol (CBD), a phytocannabinoid, exerts antidepressant-like effects in experimental animals. This study investigated the impact of CBD on sickness behavior (SB), a measure of depressive-like response, and neuro-immune changes induced by lipopolysaccharides (LPS) in mice. METHODS: Socially isolated rodents were administered with LPS to trigger SB. and treated with CBD or its vehicle. Animals were submitted to forced swimming test, to evaluate depressive-like behavior, and to open field test, to evaluate locomotory activity. Immediately after behavioral analyses, animals were euthanized and had their hypothalamus, prefrontal cortex and hippocampus dissected, to proceed neurotrophins and cytokines analyses. ELISA was used to detect IL-1ß, BDNF and NGF; and cytometric beads array to measure IL-2, IL-4, IL-6, IFN-γ, TNF-α and IL-10 levels. RESULTS: CBD effectively prevented SB-induced changes in the forced swim test without altering spontaneous locomotion. This phytocannabinoid also partially reversed LPS-evoked IL-6 increase in both the hypothalamus and hippocampus. In addition, CBD prevented endotoxin-induced increase in BDNF and NGF levels in the hippocampus of SB animals. CONCLUSIONS: Apparently, CBD prevents both behavioral and neuro-immunological changes associated with LPS-induced SB, which reinforces its potential use as an antidepressant which modulates neuroinflammation. This opens up potentially new therapeutic avenues in MDD.

Atrial Fibrillation and Use of Rivaroxaban: Performance of the Prothrombin Time / INR as a Function of Time After Blood Collection

Abstract Background Traditionally, the most effective therapy in the prevention of stroke in patients with atrial fibrillation (AF) has been oral anticoagulation with vitamin K inhibitors, particularly warfarin, whose disadvantages and adverse effects have led to their replacement by "direct oral anticoagulants", as factor X inhibitor. Objectives This study aimed to conduct a brief approach on atrial fibrillation (AF) and use of Rivaroxaban, and to comparatively evaluate the prothrombin time / International Normalized Ratio (PT/INR) in patients with AF in use of this oral anticoagulant, depending on the time elapsed between the last administration of the drug and the time of blood sample venipuncture. Methods We evaluated 34 patients with AF in use of Rivaroxaban by using PT / INR, distributed into a subgroup with blood collection time ≤ 12 hours (n = 7) and > 12 hours after the last drug intake (n = 27). Mann-Whitney test was used to compare the groups and p < 0.05 was considered significant. Results An analysis as a function of time between the Rivaroxaban intake and blood collection, revealed that PT / INR suffers the greatest effect up to 12 hours after ingestion of the drug, dropping to levels close to normal in subsequent hours before the next dose. Conclusion We concluded that, in contrast to warfarin, the knowledge of the time interval between drug intake and blood collection from patients taking Rivaroxaban is essential to properly interpret a laboratory test to assess hemostasis, particularly PT and its derivatives. Int J Cardiovasc Sci. 2020; [online].ahead print, PP.0-0

Serotonin and dopamine receptors profile on peripheral immune cells from patients with temporal lobe epilepsy.

The role of inflammation and immune cells has been demonstrated in neurological diseases, including epilepsy. Leukocytes, as well as inflammatory mediators, contribute to abnormal processes that lead to a reduction in seizure threshold and synaptic reorganization. In this sense, identifying different phenotypes of circulating immune cells is essential to understanding the role of these cells in epilepsy. Immune cells can express a variety of surface markers, including neurotransmitter receptors, such as serotonin and dopamine. Alteration in these receptors expression patterns may affect the level of inflammatory mediators and the pathophysiology of epilepsy. Therefore, in the current study, we evaluated the expression of dopamine and serotonin receptors on white blood cells from patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Blood samples from 17 patients with TLE-HS and 21 controls were collected. PBMC were isolated and stained ex vivo for flow cytometry. We evaluated the expression of serotonin (5-HT1A, 5-HT1B, 5-HT2, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4), and dopamine receptors (D1, D2, D3, D4, and D5) on the cell surface of lymphocytes and innate immune cells (monocytes and granulocytes). Our results demonstrated that innate cells and lymphocytes from patients with TLE-HS showed high mean fluorescent intensity (MFI) for 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 compared to controls. No difference was observed for 5-HT2B. For dopamine receptors, the expression of D1, D2, D4, and D5 receptors was higher on innate cells from patients with TLE-HS when compared to controls for the MFI. Regarding lymphocytes population, D2 expression was increased in patients with TLE-HS. In conclusion, there are alterations in the expression of serotonin and dopamine receptors on immune blood cells of patients with TLE-HS. Although the biological significance of these findings still needs to be further investigated, these changes may contribute to the understanding of TLE-HS pathophysiology.

Thrombin Generation and other hemostatic parameters in patients with atrial fibrillation in use of warfarin or rivaroxaban.

Patients with atrial fibrillation (AF) present hyperactivation of both platelets and coagulation leading to a hypercoagulable state which contributes to an increased risk of thromboembolism. Therefore, one of the main strategies for treatment of AF is prevention of these events through the use of oral anticoagulants (OAC). The aim of this study was to evaluate hemostasis as a whole in patients with non-valvular AF undergoing warfarin or rivaroxaban by thrombin generation test (TGT), in addition to monocyte-platelet aggregates (MPA), glycoprotein IIb/IIIa (GPIIb/IIIa), and platelet (PMP) and endothelium (EMP) microparticles, compared to age and sex matched controls. PT/INR for OAC use was also determined. In patients taking OAC, compared to control group, a decrease in TGT (p = 0.000 for all parameters) were observed. Patients taking warfarin showed to be more hypocoagulable, presenting lower levels of ETP (p = 0.000) and peak (p = 0.002) than patients using rivaroxaban. Patients on warfarin use with INR > 3 had also lower levels of ETP (p = 0.01) and peak (p = 0.006). A decrease in ETP (p = 0.03) and peak (p = 0.02) values was also observed in patients using rivaroxaban with PT > 21.4 s. Patients using warfarin (p = 0.000) and rivaroxaban (p = 0.000) presented lower levels of MPA in relation to control group. It was also observed in patients using warfarin, lower GPIIb/IIIa levels in relation to control group (p = 0.011). Patients taking rivaroxaban (p = 0.003) and warfarin (p = 0.001) had higher PMP levels compared to control group. There was no difference in levels of EMP between the groups (p = 0.0536). The present study reinforces the usefulness of OAC in AF, which decisively contribute to a better management of the disease preventing possible complications.

Evaluation of Brain Cytokines and the Level of Brain-Derived Neurotrophic Factor in an Inflammatory Model of Depression.

INTRODUCTION: Major depressive disorder is considered a global public health problem. Inflammatory processes are likely involved in its pathophysiology, but the underlying mechanisms have remained uncertain.Here, we used the model of systemic lipopolysaccharide (LPS) injection to test the hypothesis that depressive-like behaviors occur along with changes in the levels of cytokines and brain-derived neurotrophic factor (BDNF) in the hippocampus (HC), prefrontal cortex (PFC), and hypothalamus (HT), and can be prevented by dexamethasone administration. METHODS: Adult C57Bl/6 male mice were first isolated for 10 days, and thereafter received an injection of dexamethasone (6 mg/kg, intraperitoneal [i.p.]), saline followed by LPS (0.83 mg/kg, i.p.), or saline. After 6 h, animals were subjected to the forced-swim test (FST) and open-field tests. Immediately after the behavioral tests, they were euthanized and their brains were collected for the biochemical analyses. RESULTS: LPS increased the immobility time and reduced the distance travelled in the FST and open-field test, respectively. Dexamethasone increased the immobility time in saline-treated mice but reduced this behavior in the LPS group. LPS increased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and interferon (IFN)-γ in most of the regions evaluated. Dexamethasone prevented LPS-induced IL-6 in the HC, PFC, and HT. Interestingly, dexamethasone increased IL-4 and IL-10 levels in both the LPS- and saline-treated groups. Although dexamethasone reduced BDNF in saline-treated mice, it prevented LPS-induced reduction in this neurotrophic factor. CONCLUSION: In summary, dexamethasone decreased proinflammatory and increased anti-inflammatory levels of cytokines and prevented a reduction in BDNF levels induced by the inflammatory stimulus. Thus, the attenuation of depressive-like behavior induced by dexamethasone may be related to the effects on these parameters.

Comparison of Inflammatory Mediators in Patients With Atrial Fibrillation Using Warfarin or Rivaroxaban.

Background: Atrial fibrillation (AF) is the most common arrhythmia associated with high risk of venous thromboembolism. Inflammatory mechanisms may be involved in the pathophysiology of AF and in the AF-related thrombogenesis, and patients with AF might benefit from the use of anticoagulants with anti-inflammatory properties. However, the evidence is still scarce, and it points out the need of trials seeking to investigate the levels of inflammatory mediators in patients with AF under different anticoagulant therapies. Therefore, this study was designed to define whether patients with AF treated either with an activated coagulation factor X (FXa) inhibitor (rivaroxaban) or with a vitamin K inhibitor (warfarin) present changes in peripheral levels of inflammatory mediators, mainly cytokines and chemokines. Methods: A total of 127 subjects were included in this study, divided into three groups: patients with non-valvular atrial fibrillation (NVAF) using warfarin (N = 42), patients with NVAF using rivaroxaban (N = 29), and controls (N = 56). Plasma levels of inflammatory mediators were quantified by immunoassays. Results: Patients with AF (both warfarin and rivaroxaban groups) presented increased levels of inflammatory cytokines in comparison with controls. The use of rivaroxaban was associated with decreased levels of inflammatory cytokines in comparison with warfarin. On the other hand, patients with AF using rivaroxaban presented increased levels of the chemokines (MCP-1 in comparison with warfarin users; MIG and IP-10 in comparison with controls). Conclusions: AF is associated with an inflammatory profile that was less pronounced in patients on rivaroxaban in comparison with warfarin users. Further studies are necessary to assess the clinical implications of our results and whether patients with AF would benefit from rivaroxaban anti-inflammatory effects.

Inflammatory and Infectious Processes Serve as Links between Atrial Fibrillation and Alzheimer's Disease.

Atrial fibrillation (AF) is one of the most prevalent forms of arrhythmia that carries an increased risk of stroke which, in turn, is strongly associated with cognitive decline. The majority of dementia cases are caused by Alzheimer's disease (AD) with obscure pathogenesis. While the exact mechanisms are unknown, the role of inflammatory processes and infectious agents have recently been implicated in both AD and AF, suggesting a common link between these maladies. Here, we present the main shared pathways underlying arrhythmia and memory loss. The overlapping predictive biomarkers and emerging joint pharmacological approaches are also discussed.

Circulating levels of neurotrophic factors are unchanged in patients with Parkinson's disease.

There is great evidence linking neurotrophic factor (NF) dysfunction with Parkinson's disease (PD) pathophysiology. This study was conducted to evaluate plasma levels of NFs and their possible associations with clinical symptoms in PD. For this purpose, 40 PD patients and 25 controls were subjected to a clinical evaluation and peripheral blood draw. Plasma levels of brain-derived neurotrophic factor (BDNF), pro-BDNF, neurotrophin 3, neurotrophin 4, nerve growth, glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were measured by enzyme-linked immunosorbent assay. There was no significant difference between PD patients and controls regarding the plasma levels of the evaluated NFs. In addition, NF levels were not associated with disease duration, degree of motor or functional impairment, cognitive performance or severity of depressive symptoms. In conclusion, although NFs may play relevant roles in the pathophysiology of PD, the circulating levels of these molecules are not necessarily changed in patients with PD.

Circulating levels of neurotrophic factors are unchanged in patients with Parkinson's disease / Os níveis circulantes de fatores neurotróficos não estão alterados em pacientes com doença de Parkinson

ABSTRACT There is great evidence linking neurotrophic factor (NF) dysfunction with Parkinson's disease (PD) pathophysiology. This study was conducted to evaluate plasma levels of NFs and their possible associations with clinical symptoms in PD. For this purpose, 40 PD patients and 25 controls were subjected to a clinical evaluation and peripheral blood draw. Plasma levels of brain-derived neurotrophic factor (BDNF), pro-BDNF, neurotrophin 3, neurotrophin 4, nerve growth, glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were measured by enzyme-linked immunosorbent assay. There was no significant difference between PD patients and controls regarding the plasma levels of the evaluated NFs. In addition, NF levels were not associated with disease duration, degree of motor or functional impairment, cognitive performance or severity of depressive symptoms. In conclusion, although NFs may play relevant roles in the pathophysiology of PD, the circulating levels of these molecules are not necessarily changed in patients with PD.

RESUMO Há evidências de que alteracões nas ações exercidas por fatores neurotróficos (FNs) estejam associadas à fisiopatologia da doença de Parkinson (DP). O presente estudo foi conduzido para avaliar os níveis plasmáticos de FNs e suas possíveis associações com sintomas clínicos na DP. Para este fim, 40 pacientes com DP e 25 controles foram submetidos à avaliação clínica e coleta de sangue periférico. Os níveis plasmáticos do fator neurotrófico derivado do cérebro (BDNF), pro-BDNF, neurotrofina 3, neurotrofina 4, fator de crescimento do nervo, fator neurotrófico derivado da glia e fator neurotrófico ciliar foram avaliados por ensaio de imunoadsorção enzimática. Não houve diferença significativa entre pacientes com DP e controles quanto aos níveis plasmáticos dos FNs avaliados. Além disso, não encontramos associação entre os níveis dos FNs e duração da doença, grau de comprometimento motor ou funcional, desempenho cognitivo e gravidade dos sintomas depressivos. Em conclusão, embora os FNs possam desempenhar papéis relevantes na fisiopatologia da DP, os níveis circulantes dessas moléculas não estão necessariamente alterados em pacientes com DP.

Inflammation as a Possible Link Between Dyslipidemia and Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. This pathological condition is characterized not only by Aß and tau accumulation in the central nervous system (CNS), but also by inflammation, processes that can lead to neurodegeneration. Besides that, other factors may contribute to the development of AD, such as dyslipidemias. Changes in lipid levels can either influence the activity of enzymes related to the protein deposition that occurs in this pathological condition, or enhance the peripheral and CNS immune responses. Furthermore, cholesterol-associated genes are frequently associated with AD. Here, we extensively reviewed the literature and, based on the existing evidences, we suggest inflammation as an important link between dyslipidemias and AD.

Reduced Activated T Lymphocytes (CD4+CD25+) and Plasma Levels of Cytokines in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. The cause of neurodegeneration in PD is not completely understood, and evidence has shown that inflammatory/immune changes may be involved in PD pathophysiology. Herein, we aimed to determine the profile of the peripheral immune system in patients with PD in comparison with controls. Forty patients with PD and 25 age- and gender-matched controls were enrolled in this study. From these, 23 PD patients and 21 controls were included in the immunophenotyping analyses. Peripheral blood was drawn on the same day of the clinical assessment and submitted to plasma separation for enzyme-linked immunosorbent assay or cytometric bead array. Immunophenotyping analyses of the peripheral blood were performed by flow cytometry. We found that patients with PD presented peripheral immune changes evidenced by decreased percentage of T lymphocytes (CD3+ cells), especially activated T lymphocytes (CD4+CD25+ cells), when compared with controls. In line with these results, we also found decreased plasma levels of the cytokines IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17A in the PD group. In vitro experiments demonstrated that the production of cytokines by peripheral blood mononuclear cells harvested from healthy young donors was reduced after exposure to the anti-parkinsonian drugs levodopa and pramipexole. Our data corroborate the hypothesis that immunological mechanisms are involved in PD. It is not clear whether the differences that we have found are due to adaptive mechanisms or to changes associated with PD, including pharmacological treatment, or even directly related to the disease pathophysiology. Future studies are needed in this regard.

Thrombin generation assays for global evaluation of the hemostatic system: perspectives and limitations

Abstract The existing techniques to evaluate hemostasis in clinical laboratories are not sensitive enough to detect hypercoagulable and mild hypocoagulable states. Under different experimental conditions, the thrombin generation test may meet these requirements. This technique evaluates the overall balance between procoagulant and anticoagulant forces and has provided new insights in our understanding of the coagulation cascade, as well as of the diagnosis of hypocoagulability and hypercoagulability conditions. Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. The calibrated automated thrombogram method is an open system, in which different antibodies, proteins, enzymes and peptides can be introduced to answer specific questions regarding hemostatic processes. The thrombin generation test has great clinical potential, such as in monitoring patients taking anticoagulants and antiplatelet drugs, screening for genetic or acquired thrombotic disorders, and evaluating bleeding risk control in patients with hemophilia using bypass agents or replacement therapy. Different to conventional coagulation tests, the thrombin generation test can be used for an overall evaluation of hemostasis, the results of which can then be used to evaluate specific characteristics of hemostasis, such as prothrombin time, activated partial thromboplastin time, and levels of fibrinogen and other coagulation factors. The introduction of this method will contribute to a better understanding and evaluation of overall hemostatic processes; however, this method still requires standardization and clinical validation.

Thrombin generation assays for global evaluation of the hemostatic system: perspectives and limitations.

The existing techniques to evaluate hemostasis in clinical laboratories are not sensitive enough to detect hypercoagulable and mild hypocoagulable states. Under different experimental conditions, the thrombin generation test may meet these requirements. This technique evaluates the overall balance between procoagulant and anticoagulant forces and has provided new insights in our understanding of the coagulation cascade, as well as of the diagnosis of hypocoagulability and hypercoagulability conditions. Thrombin generated in the thrombin generation test can be quantified as platelet-rich or platelet-poor plasma using the calibrated automated thrombogram method, which monitors the cleavage of a fluorogenic substrate that is simultaneously compared to the known thrombin activity in a non-clotting plasma sample. The calibrated automated thrombogram method is an open system, in which different antibodies, proteins, enzymes and peptides can be introduced to answer specific questions regarding hemostatic processes. The thrombin generation test has great clinical potential, such as in monitoring patients taking anticoagulants and antiplatelet drugs, screening for genetic or acquired thrombotic disorders, and evaluating bleeding risk control in patients with hemophilia using bypass agents or replacement therapy. Different to conventional coagulation tests, the thrombin generation test can be used for an overall evaluation of hemostasis, the results of which can then be used to evaluate specific characteristics of hemostasis, such as prothrombin time, activated partial thromboplastin time, and levels of fibrinogen and other coagulation factors. The introduction of this method will contribute to a better understanding and evaluation of overall hemostatic processes; however, this method still requires standardization and clinical validation.

Peripheral levels of angiotensins are associated with depressive symptoms in Parkinson's disease.

BACKGROUND: The pathogenesis of PD remains elusive. The renin-angiotensin-system (RAS) has recently been implicated in the degeneration of dopaminergic neurons. This study aimed to compare plasma levels of components of the RAS of individuals with PD with controls. We also investigated the association between these circulating markers and motor, depressive and cognitive parameters. METHODS: Thirty PD patients and twenty controls were subjected to clinical evaluation, including cognitive and depressive symptoms assessment. Plasma levels of Angiotensin (Ang) I, Ang II, Ang- (1-7), angiotensin-converting enzyme (ACE) and ACE2 were measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: PD patients presented lower plasma levels of Ang I, Ang II and Ang- (1-7) than control individuals. Among PD patients, lower circulating levels of angiotensins were associated with increased severity of depressive symptoms. CONCLUSIONS: This is the first study showing that peripheral levels of RAS components are changed in PD and associated with depressive symptoms.

Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-ß 1-42 induced neurotoxicity and memory impairment.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Substantial evidences indicate that there is over-activation of the PI3K/Akt/mTOR axis in AD. Therefore, the aim of the present study was to investigate the effects of NVP-BEZ235 (BEZ; dactolisib), a dual PI3K/mTOR inhibitor that is under phase I/II clinical trials for the treatment of some types of cancer, in hippocampal neuronal cultures stimulated with amyloid-ß (Aß) 1-42 and in mice injected with Aß 1-42 in the hippocampus. In cell cultures, BEZ reduced neuronal death induced by Aß. BEZ, but not rapamycin, a mTOR inhibitor, or LY294002, a PI3K inhibitor that also inhibits mTOR, reduced the memory impairment induced by Aß. The effect induced by Aß was also prevented in PI3Kγ(-/-) mice. Neuronal death and microgliosis induced by Aß were reduced by BEZ. In addition, the compound increased IL-10 and TNF-α levels in the hippocampus. Finally, BEZ did not change the phosphorylation of Akt and p70s6K, suggesting that the involvement of PI3K and mTOR in the effects induced by BEZ remains controversial. Therefore, BEZ represents a potential strategy to prevent the pathological outcomes induced by Aß and should be investigated in other models of neurodegenerative conditions.

Wistar Audiogenic Rats (WAR) exhibit altered levels of cytokines and brain-derived neurotrophic factor following audiogenic seizures.

Increasing body of evidence suggests that inflammatory and neurotrophic factors might be important for epileptogenesis. Most animal studies demonstrated altered levels of these mediators in drug-induced models of seizures and epilepsy. In the present study, we investigated the production of cytokines and a neurotrophin in the brain of Wistar Audiogenic Rats (WAR), a genetic model of epilepsy, stimulated with high-intensity sound. Four hours after stimulation, animals were decapitated and the hippocampus, inferior colliculus, striatum and cortex were removed for evaluation of the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and brain derived neurotrophic factor (BDNF). All the cytokines and BDNF levels were increased in the cortex. Increased levels of TNF-α and IL-6 were also observed in the striatum. Finally, TNF-α also increased in the inferior colliculus after the seizures induced by high-intensity sound. Although different studies have demonstrated that the levels of cytokines and BDNF increase in animal models of epilepsy induced by chemical stimuli, we provided here evidence that these mediators are also increased in WAR, a genetic model of epilepsy. Thus, the observed increase in these mediators might be involved in the pathophysiology of epilepsy.