Movement strategies during obstacle crossing in people with Parkinson disease: A systematic review with meta-analysis.

OBJECTIVE: Navigating obstacles involves adjusting walking patterns, particularly when stepping over them. This task may be particularly challenging for people with Parkinson disease (PD) for several reasons. This review aims to compare the spatiotemporal gait parameters of people with and without PD while stepping over obstacles. LITERATURE SURVEY: A systematic literature search was conducted in six databases (PubMed, Scopus, Web of Science, EBSCO, Embase, and SciELO) from inception to September 2023. METHODOLOGY: Studies were selected that evaluated gait parameters of people with and without PD while walking over obstacles. Two independent researchers evaluated the eligibility and extracted gait parameters during obstacle crossing. The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Heterogeneity was assessed using I2-tests. Random effects models were determined for effect sizes as standardized mean differences (SMD). SYNTHESIS: Twenty-five studies were included in the review and 17 in the meta-analysis. Most of the studies (58%) showed a low risk of bias. People with PD exhibit a shorter step when landing after crossing an obstacle (SMD = -0.50 [-0.69 to -0.31]). Compared to people without PD, people with PD also widen their support base (SMD = 0.27 [0.07-0.47]) and reduce gait velocity (SMD = -0.60 [-0.80 to -0.39]) when crossing the obstacle. CONCLUSIONS: People with PD adopt a more conservative motor behavior during obstacle crossing than those without PD, with a shorter step length when landing after crossing an obstacle, greater step width and lower crossing speed.

Arm swing asymmetry in people with Parkinson's disease and its relationship with gait: A systematic review and meta-analysis.

BACKGROUND: Individuals with Parkinson's disease present arm swing alterations that can adversely affect their locomotion. OBJECTIVE: To identify differences in arm swing asymmetry (ASA) between individuals with Parkinson's disease (PD) and healthy individuals and to investigate the relationship between ASA, temporal-spatial gait parameters, and disease progression. METHODS: A literature search was conducted in PubMed, Scopus, ProQuest, Web of Science, and EBSCOhost up to February 2023. Cross-sectional studies evaluating parameters of arm swing (AS) and ASA were included. Methodological quality was assessed using the Critical Appraisal Checklist, and the quality of the evidence was measured with a modified Grading of Recommendations Assessment, Development, and Evaluation. RESULTS: Fourteen studies were included in the systematic review (1130 participants). Irrespective of the medication phase (ON or OFF) and the type of walk test employed, the meta-analysis showed moderate-quality evidence that individuals with PD have increased ASA amplitude (SMD = 0.84; 95% CI: 0.69, 0.99; I²= 0%).Very low-quality evidence suggests higher ASA velocity (SMD=0.64; 95% CI: 0.24, 1.05; I²=59%) and lower AS amplitude on both the most affected (ES = -1.99, 95% CI: -3.04, -0.94, I2: 91%) and the least affected sides (ES = -0.75, 95% CI: -1.05, -0.44; I²=66%). Meta-regression indicated that ASA is inversely related to disease duration (Z: -2.4892, P< 0.05) and motor symptoms progression (Z: -2.1336, P< 0.05). CONCLUSIONS: Regardless of the medication phase and the type of walk test employed, individuals with PD exhibited greater ASA and decreased AS amplitude than healthy individuals. ASA decreases as the disease progresses and symptoms worsen.

[Myelophthisis and kasabach merrit syndrome as initial manifestation of splenic angiosarcoma].

Primary splenic angiosarcoma is an extremely agressive and rare neoplasm. Manifestations as bone marrow invasion and coagulation disorders have been reported isolatedly. A 26 years-old woman presented with abdominal pain; several anemia and thrombocytopenia associated to leukoerythroblastic reaction were found in the laboratory. Consumpion coagulopathy signs and microangiopathy as schistocytes, prolonged prothrombine time, decreased fibrinogen and increased D dimer were also present. Imaging findings included a lobulated, enlarged spleen, with spontanously hyperdense areas, and heterogeneous nodules with intense, irregular enhancement after contrast administration. There were hepatic and pulmonary metastases, as well as bone lesions with conspicuous vessels. Clinical features of Kasabach-Merrit syndrome and imaging vascular neoplasm characteristics suggest a primary splenic angiosarcoma. Splenectomy and bone marrow biopsy confirmed the diagnosis of primary splenic angiosarcoma in metastatic stage.

Sistema de acciones para fortalecer el abordaje terapéutico de afecciones cardiovasculares / Action System to Strengthen the Therapeutic Approach to Cardiovascular Diseases

Introducción: las enfermedades cardiovasculares continúan ascendiendo a pesar de las potencialidades transformadoras de estilos de vida que brinda la medicina familiar. Objetivo: caracterizar la situación de salud cardiovascular, la evaluación de los recursos humanos y las necesidades organizativas para las acciones cardiovasculares y proponer un sistema de acciones para fortalecer el abordaje terapéutico de las afecciones cardiovasculares. Métodos: estudio descriptivo longitudinal retrospectivo en el policlínico "Octavio de la Concepción y la Pedraja" del municipio Camajuaní, desde septiembre 2013 a septiembre del 2014. Se trabajó con una población integrada por 79 médicos especialistas en Medicina General Integral y 12 enfermeros vinculados a la atención médica ambulatoria y de urgencia, además de los 760 pacientes con afecciones cardiovasculares. Se utilizaron variables como: nivel de conocimiento, desempeño y factores de riesgo. Resultados: no hubo diferencia entre los grupos de edades (p> 0,05), con predominio del sexo masculino (p< 0,01), el mayor por ciento se encontraba por encima del 90 percentil (p< 0,001), con predominio del sedentarismo y antecedentes familiares de la enfermedad (p< 0,001). En el conocimiento de la temática resultó bien en los profesionales médicos, con un valor muy altamente significativo (p< 0,001), y en el desempeño predominó la calificación de BIEN, con una significación a la prueba p= 0,000. Conclusiones: la atención ambulatoria y de urgencia al paciente descompensado por afecciones cardiovasculares fue satisfactoria. Los pacientes en riesgo no desarrollan un adecuado proceso de rehabilitación comunitaria y continúan sufriendo descompensaciones(AU)

Introduction: cardiovascular diseases still have a growing rate in Cuba, but due to the possibilities the family medicine has of changing people´s life styles, and the role of doctors as promotors of a sanitary culture, it is possible to act upon risk factors, avoiding the emergence of cardiovascular diseases. Objective: to propose a system of actions to strengthen the management of cardiovascular diseases in the Primary Health Care. Methods: it was used a retrospective longitudinal descriptive method in Octavio de la Concepcion y la Pedraja Policlinic in Camajuani, from September 2013 to September 2014. The target population for this research consisted in 79 physicians, specialists in Integral General Medicine, and 12 nurses linked to ambulatoty and emergency health care, in addition to 760 patients suffering from cardiovascular conditions. The variables were level of knowledge about the topic, performance and risk factors. The information was gathered through the patients´medical records, the records of patients who had been admitted to the intensive care unit of the municipal policlinic, the records of death certificates, observation guides, surveys applied to professionals linked to Primary Health Care, interview to experts. Results: there was a difference among the age groups (p> 0.005), prevailing the male sex (p< 0.01), the highest percentage was above percentile 90 (p< 0.001), sedentarism and antecedents of the disease in the family history were predominant (p< 0.001). A qualification of GOOD was prevalent among the health professionals with a highly significant value of probability (p< 0.001) when evaluating knowledge about the topic, the performance in both groups of professionals was graded predominantly as GOOD with a signification to the test (p= 0.000). Conclusions: the ambulatory and emergency health care to decompensated patients suffering from cardiovascular diseases was satisfactry, the patients at risk continue suffering decompensations and they do not develop an appropriate process of communitary rehabilitation(AU)

REM sleep deprivation reverses neurochemical and other depressive-like alterations induced by olfactory bulbectomy.

There is compelling evidence that sleep deprivation (SD) is an effective strategy in promoting antidepressant effects in humans, whereas few studies were performed in relevant animal models of depression. Acute administration of antidepressants in humans and rats generates a quite similar effect, i.e., suppression of rapid eye movement (REM) sleep. Then, we decided to investigate the neurochemical alterations generated by a protocol of rapid eye movement sleep deprivation (REMSD) in the notably known animal model of depression induced by the bilateral olfactory bulbectomy (OBX). REMSD triggered antidepressant mechanisms such as the increment of brain-derived neurotrophic factor (BDNF) levels, within the substantia nigra pars compacta (SNpc), which were strongly correlated to the swimming time (r = 0.83; P < 0.0001) and hippocampal serotonin (5-HT) content (r = 0.66; P = 0.004). Moreover, there was a strong correlation between swimming time and hippocampal 5-HT levels (r = 0.70; P = 0.003), strengthen the notion of an antidepressant effect associated to REMSD in the OBX rats. In addition, REMSD robustly attenuated the hippocampal 5-HT deficiency produced by the OBX procedure. Regarding the rebound (REB) period, we observed the occurrence of a sustained antidepressant effect, indicated mainly by the swimming and climbing times which could be explained by the maintenance of the increased nigral BDNF expression. Hence, hippocampal 5-HT levels remained enhanced in the OBX group after this period. We suggested that the neurochemical complexity inflicted by the OBX model, counteracted by REMSD, is directly correlated to the nigral BDNF expression and hippocampal 5-HT levels. The present findings provide new information regarding the antidepressant mechanisms triggered by REMSD.

Experimental Lung Injury Promotes Changes in Oxidative/Nitrative Status and Inflammatory Markers in Cerebral Cortex of Rats.

In the present study, we investigate the effect of lung injury on parameters of oxidative/nitrative stress [reactive oxygen species production, nitrite levels, thiobarbituric acid-reactive substances (TBARS), carbonyl content, sulfhydryl content, activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), total radical-trapping antioxidant potential, glutathione content, and glucose-6-phosphate dehydrogenase], as well as on inflammation mediators [immunocontent of nuclear factor-kappaB (NF-κB) total (p65), NF-κB phosphorylated (pp65) subunit (cytosolic and nuclear), TNF-α, IL-1ß, IL-6, and IL-10] in the cerebral cortex. Cytokine levels in serum were also evaluated. Adult Wistar rats were submitted to lung injury induced by intratracheal instillation of lipopolysaccharide in a dose of 100 µg/100 g body weight. Sham group (control) received isotonic saline instillation. Twelve hours after the injury, rats were decapitated and blood samples were collected and the cerebral cortex dissected out. Results showed an increase in reactive oxygen species production, TBARS, and nitrite and carbonyl levels in the cerebral cortex of rats submitted to lung injury. Antioxidant enzymatic defenses were altered, superoxide dismutase and glutathione peroxidase activities decreased, and catalase activity increased. Non-enzymatic antioxidant capacity, glutathione content, and glucose-6-phosphate dehydrogenase were decreased. Inflammatory parameters were also altered in the cerebral cortex of rats subjected to lung injury; it was observed an increase in the immunocontent of NF-κB/p65 (nuclear fraction) and NF-κB/pp65 (cytosolic and nuclear faction), as well as an increase in TNF-α, IL-1ß, IL-6, and IL-10 levels. The levels of IL-10 also increased in the serum. Our findings show that the lung injury alters oxidative/nitrative status and induces inflammation in the cerebral cortex of rats, which might be associated with cognitive impairments present in patients with lung injury.

Sistema de acciones para fortalecer el abordaje terapéutico de afecciones cardiovasculares / Action System to Strengthen the Therapeutic Approach to Cardiovascular Diseases

Introducción: las enfermedades cardiovasculares continúan ascendiendo a pesar de las potencialidades transformadoras de estilos de vida que brinda la medicina familiar. Objetivo: caracterizar la situación de salud cardiovascular, la evaluación de los recursos humanos y las necesidades organizativas para las acciones cardiovasculares y proponer un sistema de acciones para fortalecer el abordaje terapéutico de las afecciones cardiovasculares. Métodos: estudio descriptivo longitudinal retrospectivo en el policlínico Octavio de la Concepción y la Pedraja del municipio Camajuaní, desde septiembre 2013 a septiembre del 2014. Se trabajó con una población integrada por 79 médicos especialistas en Medicina General Integral y 12 enfermeros vinculados a la atención médica ambulatoria y de urgencia, además de los 760 pacientes con afecciones cardiovasculares. Se utilizaron variables como: nivel de conocimiento, desempeño y factores de riesgo. Resultados: no hubo diferencia entre los grupos de edades (p> 0,05), con predominio del sexo masculino (p< 0,01), el mayor por ciento se encontraba por encima del 90 percentil (p< 0,001), con predominio del sedentarismo y antecedentes familiares de la enfermedad (p< 0,001). En el conocimiento de la temática resultó bien en los profesionales médicos, con un valor muy altamente significativo (p< 0,001), y en el desempeño predominó la calificación de BIEN, con una significación a la prueba p= 0,000...

Introduction: cardiovascular diseases still have a growing rate in Cuba, but due to the possibilities the family medicine has of changing people´s life styles, and the role of doctors as promotors of a sanitary culture, it is possible to act upon risk factors, avoiding the emergence of cardiovascular diseases. Objective: to propose a system of actions to strengthen the management of cardiovascular diseases in the Primary Health Care. Methods: it was used a retrospective longitudinal descriptive method in Octavio de la Concepcion y la Pedraja Policlinic in Camajuani, from September 2013 to September 2014. The target population for this research consisted in 79 physicians, specialists in Integral General Medicine, and 12 nurses linked to ambulatoty and emergency health care, in addition to 760 patients suffering from cardiovascular conditions. The variables were level of knowledge about the topic, performance and risk factors. The information was gathered through the patients´medical records, the records of patients who had been admitted to the intensive care unit of the municipal policlinic, the records of death certificates, observation guides, surveys applied to professionals linked to Primary Health Care, interview to experts. Results: there was a difference among the age groups (p› 0.005), prevailing the male sex (p‹ 0.01), the highest percentage was above percentile 90 (p‹ 0.001), sedentarism and antecedents of the disease in the family history were predominant (p‹ 0.001). A qualification of GOOD was prevalent among the health professionals with a highly significant value of probability (p‹ 0.001) when evaluating knowledge about the topic, the performance in both groups of professionals was graded predominantly as GOOD with a signification to the test (p= 0.000)...

Evaluation of Na+, K+-ATPase activity in the brain of young rats after acute administration of fenproporex

Objectives: Fenproporex is an amphetamine-based anorectic which is rapidly converted into amphetamine in vivo. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that the effects of fenproporex on brain metabolism are poorly known and that Na+, K+-ATPase is essential for normal brain function, this study sought to evaluate the effect of this drug on Na+, K+-ATPase activity in the hippocampus, hypothalamus, prefrontal cortex, and striatum of young rats. Methods: Young male Wistar rats received a single injection of fenproporex (6.25, 12.5, or 25 mg/kg intraperitoneally) or polysorbate 80 (control group). Two hours after the last injection, the rats were killed by decapitation and the brain was removed for evaluation of Na+, K+-ATPase activity. Results: Fenproporex decreased Na+, K+-ATPase activity in the striatum of young rats at doses of 6.25, 12.5, and 25 mg/kg and increased enzyme activity in the hypothalamus at the same doses. Na+, K+-ATPase activity was not affected in the hippocampus or prefrontal cortex. Conclusion: Fenproporex administration decreased Na+, K+-ATPase activity in the striatum even in low doses. However, in the hypothalamus, Na+, K+-ATPase activity was increased. Changes in this enzyme might be the result of the effects of fenproporex on neuronal excitability. .

Coumestrol treatment prevents Na+, K+ -ATPase inhibition and affords histological neuroprotection to male rats receiving cerebral global ischemia.

OBJECTIVE: In this study, we investigated the possible mechanisms underlying the neuroprotective effects of coumestrol, a potent isoflavonoid with antioxidant activities and binding affinities for both estrogen receptors (ER) ER-alpha and ER-beta that are comparable to those of 17beta-estradiol, in a model of global ischemia in male subjects. METHODS: Wistar rats underwent global ischemia (10 minutes) or sham surgery and received a single intracerebroventricular (icv) infusion of 20 µg of coumestrol or vehicle 1 hour before ischemia or 0, 3, 6, or 24 hours after reperfusion. RESULTS: The data analysis revealed an extensive neuronal death in the CA1 hippocampal subfield at 7 days, and a significant decrease in the Na+, K+ -ATPase activity at 1 and 24 hours after ischemia, and both injuries were attenuated by coumestrol administration. CONCLUSIONS: Coumestrol treatment was effective in preventing neuronal loss in all times of administration as well as able to rescue the Na+, K+ -ATPase activity, suggesting its potential benefits for either prevention or therapeutics use against cerebral ischemia in males.

Experimental lung injury promotes alterations in energy metabolism and respiratory mechanics in the lungs of rats: prevention by exercise.

In the present study we investigated the effects of lung injury on energy metabolism (succinate dehydrogenase, complex II, cytochrome c oxidase, and ATP levels), respiratory mechanics (dynamic and static compliance, elastance and respiratory system resistance) in the lungs of rats, as well as on phospholipids in bronchoalveolar lavage fluid. The protective effect of physical exercise on the alterations caused by lung injury, including lung edema was also evaluated. Wistar rats were submitted to 2 months of physical exercise. After this period the lung injury was induced by intratracheal instillation of lipopolysaccharide. Adult Wistar rats were submitted to 2 months of physical exercise and after this period the lung injury was induced by intratracheal instillation of lipopolysaccharide in dose 100 µg/100 g body weight. The sham group received isotonic saline instillation. Twelve hours after the injury was performed the respiratory mechanical and after the rats were decapitated and samples were collected. The rats subjected to lung injury presented a decrease in activities of the enzymes of the electron transport chain and ATP levels in lung, as well as the formation of pulmonary edema. A decreased lung dynamic and static compliance, as well as an increase in respiratory system resistance, and a decrease in phospholipids content were observed. Physical exercise was able to totally prevent the decrease in succinate dehydrogenase and complex II activities and the formation of pulmonary edema. It also partially prevented the increase in respiratory system resistance, but did not prevent the decrease in dynamic and static compliance, as well as in phospholipids content. These findings suggest that the mitochondrial dysfunction may be one of the important contributors to lung damage and that physical exercise may be beneficial in this pathology, although it did not prevent all changes present in lung injury.

Evaluation of Na+, K+-ATPase activity in the brain of young rats after acute administration of fenproporex.

OBJECTIVES: Fenproporex is an amphetamine-based anorectic which is rapidly converted into amphetamine in vivo. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that the effects of fenproporex on brain metabolism are poorly known and that Na+, K+-ATPase is essential for normal brain function, this study sought to evaluate the effect of this drug on Na+, K+-ATPase activity in the hippocampus, hypothalamus, prefrontal cortex, and striatum of young rats. METHODS: Young male Wistar rats received a single injection of fenproporex (6.25, 12.5, or 25 mg/kg intraperitoneally) or polysorbate 80 (control group). Two hours after the last injection, the rats were killed by decapitation and the brain was removed for evaluation of Na+, K+-ATPase activity. RESULTS: Fenproporex decreased Na+, K+-ATPase activity in the striatum of young rats at doses of 6.25, 12.5, and 25 mg/kg and increased enzyme activity in the hypothalamus at the same doses. Na+, K+-ATPase activity was not affected in the hippocampus or prefrontal cortex. CONCLUSION: Fenproporex administration decreased Na+, K+-ATPase activity in the striatum even in low doses. However, in the hypothalamus, Na+, K+-ATPase activity was increased. Changes in this enzyme might be the result of the effects of fenproporex on neuronal excitability.

Does Parkinson's disease and type-2 diabetes mellitus present common pathophysiological mechanisms and treatments?

Parkinson's disease (PD) is the second most common neurodegenerative disease afflicting about 1% of people over 65 years old and 4-5% of people over 85 years. It is proposed that a cascade of deleterious factors is set in motion within that neuron made not of one, but rather of multiple factors such as free radicals, excitotoxicity, neuroinflammation, and apoptosis to cite only some of the most salient. In this scenario, chronic systemic inflammation, as well as impaired mitochondrial metabolism, have also been suspected of playing a role in the development of type-2 diabetes, and the possibility of a shared pathophysiology of PD and type-2 diabetes has been proposed. The discussion about the interactions between PD and type-2 diabetes mellitus began in the 1960's and there is still controversy. Insulin and dopamine may exert reciprocal regulation hence; hypoinsulinemia induced by streptozotocin decreased the amounts of dopamine transporter and tyrosine hydroxylase transcripts in the substantia nigra pars compacta. Accordingly, dopamine depletion in the striatum is able to decreases insulin signaling in basal ganglia, indicating that, perhaps, PD may be considered as a risk factor for the development of type-2 diabetes mellitus. In this sense, it is described that peroxisome proliferator-activated receptor-γ, ATP-sensitive K(+) channels, AMP-activated protein kinase, glucagon-like peptide-1 and dipeptidyl peptidase-4 are important therapeutic targets for PD and reinforces the association with diabetes. Therefore, the objective of the present review is to contextualize the mutual pathophysiological interactions between PD and type-2 diabetes mellitus, as well as the potential common treatments.

The effect of exercise on the oxidative stress induced by experimental lung injury.

AIM: The effects of physical exercise on oxidative stress parameters and immunocontent of NF-кß/p65 in lung of rats submitted to lung injury, as well as its possible protective effect on the changes in the alveolar-capillary barrier (total cell count, lactate dehydrogenase and total protein) in the bronchoalveolar lavage fluid (BALF) and the inflammatory infiltration in the pulmonary parenchyma were evaluated. MAIN METHODS: Wistar rats were submitted to two months of physical exercise and after this period, lung injury was induced by intratracheal instillation of lipopolysaccharide (dose of 100 µg/100 g body weight). Twelve hours after injury, the animals were sacrificed and lung and BALF were collected. KEY FINDINGS: Results showed an increase in reactive species production, lipid peroxidation, oxidative damage to protein, as well as in nitrite levels and NF-кß/p65 immunocontent in lung of rats submitted to lung injury. Physical exercise was able to totally prevent the increase in reactive species, nitrite levels and NF-кß/p65 immunocontent, but partially prevented the damage to protein. Superoxide dismutase and catalase were not changed in lung injury group, but the activities of these enzymes were increased in lung injury plus exercise group. Non-enzymatic antioxidant capacity, glutathione content and glutathione peroxidase were decreased and exercise totally prevented such effects. Rats subjected to lung injury presented an increase in total cell, lactate dehydrogenase and total protein; exercise partially prevented the increase in lactate dehydrogenase. SIGNIFICANCE: These findings suggest that physical exercise may prevent, at least partially, the oxidative damage caused by experimental lung injury, suggesting that exercise may have an important role as protector in this condition.

Cytoskeleton of cortical astrocytes as a target to proline through oxidative stress mechanisms.

Hyperprolinemia is an inherited disorder of proline (Pro) metabolism and patients affected by this disease may present neurological manifestations. However, the mechanisms of neural excitotoxicity elicited by hyperprolinemia are far from being understood. Considering the pivotal role of cytoskeletal remodeling in several neurodegenerative pathologies and the potential links between cytoskeleton, reactive oxygen species production and cell death, the aim of the present work was to study the effects of Pro on astrocyte and neuron cytoskeletal remodeling and the possible oxidative stress involvement. Pro induced a shift of actin cytoskeleton in stress fibers together with increased RhoA immunocontent and ERK1/2 phosphorylation/activation in cortical astrocytes. Unlike astrocytes, results evidenced little susceptibility of neuron cytoskeleton remodeling, since Pro-treated neurons presented unaltered neuritogenesis. We observed increased hydrogen peroxide production characterizing oxidative stress together with decreased superoxide dismutase (SOD) and catalase (CAT) activities in cortical astrocytes after Pro treatment, while glutathione peroxidase (GSHPx) activity remained unaltered. However, coincubation with Pro and Trolox/melatonin prevented decreased SOD and CAT activities in Pro-treated astrocytes. Accordingly, these antioxidants were able to prevent the remodeling of the actin cytoskeleton, RhoA increased levels and ERK1/2 phosphorylation in response to high Pro exposure. Taken together, these findings indicated that the cytoskeleton of cortical astrocytes, but not of neurons in culture, is a target to Pro and such effects could be mediated, at least in part, by redox imbalance, RhoA and ERK1/2 signaling pathways. The vulnerability of astrocyte cytoskeleton may have important implications for understanding the effects of Pro in the neurotoxicity linked to inborn errors of Pro metabolism.

Evidence that AKT and GSK-3ß pathway are involved in acute hyperhomocysteinemia.

Homocysteine is a neurotoxic amino acid that accumulates in several disorders including homocystinuria, neurodegenerative and neuroinflammatory diseases. In the present study we evaluated the effect of acute and chronic hyperhomocysteinemia on Akt, NF-κB/p65, GSK-3ß, as well as Tau protein in hippocampus of rats. For acute treatment, rats received a single injection of homocysteine (0.6 µmol/g body weight) or saline (control). For chronic treatment, rats received daily subcutaneous injections of homocysteine (0.3-0.6 µmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12h after the last injection, rats were euthanized, the hippocampus was removed and samples were submitted to electrophoresis followed by Western blotting. Results showed that acute hyperhomocysteinemia increases Akt phosphorylation, cytosolic and nuclear immunocontent of NF-κB/p65 subunit and Tau protein phosphorylation, but reduces GSK-3ß phosphorylation at 1h after homocysteine injection. However, 12h after acute hyperhomocysteinemia there is no effect on Akt and GSK-3ß phosphorylation. Furthermore, chronic hyperhomocysteinemia did not alter Akt and GSK-3ß phosphorylation at 1h and 12h after the last administration of this amino acid. Our data showed that Akt, NF-κB/p65, GSK-3ß and Tau protein are activated in hippocampus of rats subjected to acute hyperhomocysteinemia, suggesting that these signaling pathways may be, at least in part, important contributors to the neuroinflammation and/or brain dysfunction observed in some hyperhomocystinuric patients.

Chronic hyperhomocysteinemia increases inflammatory markers in hippocampus and serum of rats.

This study investigated the effects of chronic homocysteine administration on some parameters of inflammation, such as cytokines (TNF-α, IL-1ß and IL-6), chemokine CCL(2) (MCP-1), nitrite and prostaglandin E(2) levels, as well as on immunocontent of NF-κB/p65 subunit in hippocampus and/or serum of rats. Since acetylcholinesterase has been associated with inflammation, we also evaluated the effect of homocysteine on this enzyme activity in hippocampus of rats. Wistar rats received daily subcutaneous injections of homocysteine (0.3-0.6 µmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12 h after the last injection, rats were euthanized and hippocampus and serum were used. Results showed that chronic hyperhomocysteinemia significantly increased pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), chemokine CCL(2) (MCP-1) and prostaglandin E(2) in hippocampus and serum of rats at 1 and 12 h after the last injection of homocysteine. Nitrite levels increased in hippocampus, but decreased in serum at 1 h after chronic hyperhomocysteinemia. Acetylcholinesterase activity and immunocontent of citoplasmic and nuclear NF-κB/p65 subunit were increased in hippocampus of rats subjected to hyperhomocysteinemia at 1 h, but did not alter at 12 h after the last injection of homocysteine. According to our results, chronic hyperhomocysteinemia increases inflammatory parameters, suggesting that this process might be associated, at least in part, with the cerebrovascular and vascular dysfunctions characteristic of some homocystinuric patients.

Physical exercise reverses glutamate uptake and oxidative stress effects of chronic homocysteine administration in the rat.

The influence of physical exercise on the effects elicited by homocysteine on glutamate uptake and some parameters of oxidative stress, namely thiobarbituric acid-reactive substances, 2',7'-dichlorofluorescein (H(2)DCF) oxidation, as well as enzymatic antioxidant activities, superoxide dismutase, catalase and glutathione peroxidase in rat cerebral cortex were investigated. Wistar rats received subcutaneous administration of homocysteine or saline (control) from the 6th to 29th day of life. The physical exercise was performed from the 30th to 60th day of life; 12 h after the last exercise session animals were sacrificed and the cerebral cortex was dissected out. It is shown that homocysteine reduces glutamate uptake increases thiobarbituric acid-reactive substances and disrupts enzymatic antioxidant defenses in cerebral cortex. Physical activity reversed the homocysteine effects on glutamate uptake and on antioxidant enzymes activities; although the increase in thiobarbituric acid-reactive substances was only partially reversed by exercise. These findings allow us to suggest that physical exercise may have a protective role against homocysteine-induced oxidative imbalance and brain damage to the glutamatergic system.

Evidence that hyperprolinemia alters glutamatergic homeostasis in rat brain: neuroprotector effect of guanosine.

This study investigated the effects of acute and chronic hyperprolinemia on glutamate uptake, as well as some mechanisms underlying the proline effects on glutamatergic system in rat cerebral cortex. The protective role of guanosine on effects mediated by proline was also evaluated. Results showed that acute and chronic hyperprolinemia reduced glutamate uptake, Na(+), K(+)-ATPase activity, ATP levels and increased lipoperoxidation. GLAST and GLT-1 immunocontent were increased in acute, but not in chronic hyperprolinemic rats. Our data suggest that the effects of proline on glutamate uptake may be mediated by lipid peroxidation and disruption of Na(+), K(+)-ATPase activity, but not by decreasing in glutamate transporters. This probably induces excitotoxicity and subsequent energy deficit. Guanosine was effective to prevent most of the effects promoted by proline, reinforcing its modulator role in counteracting the glutamate toxicity. However, further studies are needed to assess the modulatory effects of guanosine on experimental hyperprolinemia.

Acute hyperhomocysteinemia alters the coagulation system and oxidative status in the blood of rats.

In the present study, we investigated the effect of the acute administration of homocysteine (Hcy) on parameters of the coagulation system, as well as fibrinogen and nitrite levels in the blood of rats. In addition, we evaluated the effect of acute hyperhomocysteinemia on thiobarbituric acid-reactive substances in plasma and on antioxidant enzymes activities (superoxide dismutase, catalase, and gluthatione peroxidase) in the erythrocytes of rats. Wistar rats, aged 29 days, received a single subcutaneous dorsal injection of saline (control) or Hcy (0.6 µmol/g body weight). Fifteen minutes, 1 h, 6 h or 12 h after the injection, the rats were euthanized and the blood, plasma, and erythrocytes were collected. Results showed that Hcy significantly increased platelet count in the blood and plasma fibrinogen levels of rats at 15 min and 1 h, but not at 6 h and 12 h, when compared with the control group. Prothrombin time, activated partial thromboplastin time, and nitrite levels significantly decreased in plasma at 15 min and 1 h, but not at 6 h and 12 h after Hcy administration. In addition, hyperhomocysteinemia increased thiobarbituric acid-reactive, an index of lipid peroxidation, in plasma at 15 min and 1 h; decreased the superoxide dismutase and gluthatione peroxidase activity, and increased the catalase activity at 15 min in erythrocytes of rats, suggesting that acute Hcy administration may alter the oxidative status in the blood of rats. Our findings suggest that hypercoagulability and oxidative stress can occur after acute hyperhomocysteinemia, possibly in association, at least in part, with the vascular dysfunction and thromboembolic complications observed in homocystinuric patients.

Physical exercise reverses cognitive impairment in rats subjected to experimental hyperprolinemia.

This study investigated whether physical exercise would reverse proline-induced performance deficits in water maze tasks, as well as its effects on brain-derived neurotrophic factor (BDNF) immunocontent and brain acetylcholinesterase (AChE) activity in Wistar rats. Proline administration followed partial time (6th-29th day of life) or full time (6th-60th day of life) protocols. Treadmill exercise was performed from 30th to 60th day of life, when behavioral testing was started. After that, animals were sacrificed for BDNF and AChE determination. Results show that proline impairs cognitive performance, decreases BDNF in cerebral cortex and hippocampus and increases AChE activity in hippocampus. All reported effects were prevented by exercise. These results suggest that cognitive, spatial learning/memory, deficits caused by hyperprolinemia may be associated, at least in part, to the decrease in BDNF levels and to the increase in AChE activity, as well as support the role of physical exercise as a potential neuroprotective strategy.