Increased ATP release and CD73-mediated adenosine A2A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction.

Extracellular ATP is a danger signal to the brain and contributes to neurodegeneration in animal models of Alzheimer's disease through its extracellular catabolism by CD73 to generate adenosine, bolstering the activation of adenosine A2A receptors (A2AR). Convulsive activity leads to increased ATP release, with the resulting morphological alterations being eliminated by A2AR blockade. However, it is not known if upon convulsions there is a CD73-mediated coupling between ATP release and A2AR overactivation, causing neurodegeneration. We now show that kainate-induced convulsions trigger a parallel increase of ATP release and of CD73 and A2AR densities in synapses and astrocytes of the mouse hippocampus. Notably, the genetic deletion of CD73 attenuates neuronal degeneration but has no impact on astrocytic modifications in the hippocampus upon kainate-induced convulsions. Furthermore, kainate-induced convulsions cause a parallel deterioration of hippocampal long-term potentiation (LTP) and hippocampal-dependent memory performance, which is eliminated by knocking out CD73. This demonstrates the key role of the ATP release/CD73/A2AR pathway to selectively control synaptic dysfunction and neurodegeneration following an acute brain insult, paving the way to consider CD73 as a new therapeutic target to prevent neuronal damage upon acute brain damage.

Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress.

Increased ATP release and its extracellular catabolism through CD73 (ecto-5'-nucleotidase) lead to the overactivation of adenosine A2A receptors (A2AR), which occurs in different brain disorders. A2AR blockade blunts mood and memory dysfunction caused by repeated stress, but it is unknown if increased ATP release coupled to CD73-mediated formation of extracellular adenosine is responsible for A2AR overactivation upon repeated stress. This was now investigated in adult rats subject to repeated stress for 14 consecutive days. Frontocortical and hippocampal synaptosomes from stressed rats displayed an increased release of ATP upon depolarization, coupled to an increased density of vesicular nucleotide transporters and of CD73. The continuous intracerebroventricular delivery of the CD73 inhibitor α,ß-methylene ADP (AOPCP, 100 µM) during restraint stress attenuated mood and memory dysfunction. Slice electrophysiological recordings showed that restraint stress decreased long-term potentiation both in prefrontocortical layer II/III-layer V synapses and in hippocampal Schaffer fibers-CA1 pyramid synapses, which was prevented by AOPCP, an effect occluded by adenosine deaminase and by the A2AR antagonist SCH58261. These results indicate that increased synaptic ATP release coupled to CD73-mediated formation of extracellular adenosine contributes to mood and memory dysfunction triggered by repeated restraint stress. This prompts considering interventions decreasing ATP release and CD73 activity as novel strategies to mitigate the burden of repeated stress.

Biochemical characterization of an ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP, E.C. 3.1.4.1) from rat cardiac soluble and microsomal fractions.

In this study, we have reported the kinetic and biochemical characterization of ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) activity in rat cardiac fractions, one soluble and the other enriched in vesicles derived from sarcoplasmic reticulum. Both fractions demonstrated E-NPP activities, which could be observed by extracellular hydrolysis of p-nitrophenyl-5'-thymidine monophosphate (p-Nph-5'-TMP) and other biochemical characteristics. The K(M) values for the hydrolysis of p-Nph-5'-TMP in soluble and microsomal fractions were 118.53 ± 27.28 and 91.92 ± 12.49 µM, respectively. The V(max) values calculated were 2.56 ± 0.15 and 113.87 ± 21.09 nmol p-nitrophenol/min/mg of protein in soluble and microsomal fractions, respectively. Among the compounds tested to evaluate the possible activity of other enzymes on p-Nph-5'-TMP hydrolysis, only suramin (0.25 mM) produced a significant inhibition of substrate hydrolysis. Thus, our results strongly suggest the presence of E-NPP enzymes in subcellular fractions of rat heart, which could be involved in nucleotide signalling in the cardiac tissue.

Gestational purple grape juice consumption does not change fetal ductus arteriosus constriction in Wistar rats.

Grape juice consumption may influence the early occurrence of ductal constriction during pregnancy, since the consumption of foods rich in polyphenols can be linked to the premature constriction of the ductus arteriosus. This study aimed to evaluate the effect of purple grape juice consumption during gestation on fetal ductus arteriosus closure, prostaglandin levels, and oxidative stress markers in Wistar rats. We divided 18 pregnant rats into four groups: a control group (C), a single-dose grape juice group (SDGJ), a two-dose grape juice group (TDGJ) of 7 µl/g body weight per day, and an indomethacin group (I). Blood was collected on gestational day (GD) 0, 14, and 20. Prostaglandin levels were measured, and the livers and hearts were removed from the mothers and fetuses for oxidative stress analysis; histology of the fetal ductus arteriosus was performed. Prostaglandin levels (pg/ml) at GD 20 were (C:1462.10 ± 314.61); (SDGJ:987.66 ± 86.25); (TDGJ:1290.00 ± 221.57), and (I:584.75 ± 46.77). Fetal ductus arteriosus closure occurred only in the indomethacin group. Lipid peroxidation evaluated through thiobarbituric acid reactive substances (nmol/mg protein) in maternal livers was lower in the grape juice groups (C: 4.11 ± 0.76 nmol/mg protein), (SDGJ: 2.34 ± 0.36), (TDGJ: 1.52 ± 0.18), and (I: 4.20 ± 0.76). Sulfhydryls (nmol/mg protein) were lower in the TDGJ group (C:763.59 ± 61.38 nmol/mg protein), (SDGJ:978.88 ± 158.81), (TDGJ:385.32 ± 86.78), and (I:727.72 ± 49.12). Also, superoxide dismutase activity (USOD/mg protein) was higher in fetal hearts in this group: (C:5.29 ± 0.33), (SDGJ:4.48 ± 0.47), (TDGJ:7.35 ± 0.43), and (I:6.00 ± 0.18). We conclude that grape juice consumption in pregnancy does not induce ductus arteriosus closure in the fetus and presented potential antioxidant effects.

The hydrolysis of striatal adenine- and guanine-based purines in a 6-hydroxydopamine rat model of Parkinson's disease.

Parkinson's disease (PD) is characterized by a progressive neurodegeneration in the substantia nigra and a striatal dopamine decrease. Striatal extracellular adenosine and ATP modulate the dopaminergic neurotransmission whereas guanosine has a protective role in the brain. Therefore, the regulation of their levels by enzymatic activity may be relevant to the clinical feature of PD. Here it was evaluated the extracellular nucleotide hydrolysis from striatal slices 4 weeks after a unilateral infusion with 6-OHDA into the medial forebrain bundle. This infusion increased ADP, AMP, and GTP hydrolysis by 15, 25, and 41%, respectively, and decreased GDP hydrolysis by 60%. There was no change in NTPDases1, 2, 3, 5, 6, and 5'-nucleotidase transcription. Dopamine depletion changes nucleotide hydrolysis and, therefore, alters the regulation of striatal nucleotide levels. These changes observed in 6-OHDA-lesioned animals may contribute to the symptoms observed in the model and provide evidence to indicate that extracellular purine hydrolysis is a key factor in understanding PD, giving hints for new therapies.

Maternal resistance exercise promotes changes in neuroplastic and epigenetic marks of offspring's hippocampus during adult life.

Studies indicate that gestational exercise practice positively impacts the offspring's cognition. Nevertheless, the influence of maternal resistance exercise, different periods of exercise practice, and the inter- and transgenerational effects involved in these responses are not known. This study sought to report the influence of the maternal practice of resistance exercise on offspring's cognitive function, exploring behavior, and neuroplastic and epigenetic marks in the hippocampus. Female Wistar rats were divided into four groups: sedentary (SS), exercised during pregnancy (SE), exercised before pregnancy (ES), and exercised before and during pregnancy (EE). Exercised rats were submitted to a resistance exercise protocol (vertical ladder climbing). Between postnatal days (P)81 and P85, male offspring were submitted to the Morris water maze test. At P85, the following analyses were performed in offspring's hippocampus: expression of IGF-1 and BrdU+ cells, global DNA methylation, H3/H4 acetylation, and HDAC2 amount. Only the offspring of SE mothers presented subtly better performance on learning and memory tasks, associated with lower HDAC2 amount. Offspring from ES mothers presented an overexpression of hippocampal neuroplastic marks (BrdU+ and IGF-1), as well as a decrease of DNA methylation and an increase in H4 acetylation. Offspring from EE mothers (continuously exercised) did not present modifications in plasticity or epigenetic parameters. This is the first study to observe the influence of maternal resistance exercise on offspring's brains. The findings provide evidence that offspring's hippocampus plasticity is influenced by exercise performed in isolated periods (pre- or gestationally) more than that performed continually.

The use of retinoic acid in association with microneedling in the treatment of epidermal melasma: efficacy and oxidative stress parameters.

This study aimed to evaluate the effectiveness of isolated treatment with retinoic acid and its combination with the microneedling technique in facial melasma, seeking to associate these results with possible oxidative damage. This is a blinded randomized clinical trial with 42 women with facial melasma (skin phototype I-IV), randomized into Group A (microneedling and 5% retinoic acid) or Group B (5% retinoic acid alone). Four procedures were applied with 15 days intervals (4 blood collections). Clinical improvement was assessed using the Melasma Area Severity Index (MASI). Serum oxidative stress levels were evaluated by protein oxidation (carbonyl), lipid peroxidation (TBARS) and sulfhydryl groups, as well as enzyme activities of superoxide dismutase (SOD) and catalase (CAT). The statistical analyzes were performed by generalized estimation equation (GEE). There was a reduction in MASI scale and TBARS levels in both groups over time (p < 0.05), with no difference between groups (p = 0.416). There was also a substantial increase in the carbonyl levels at 30 days (p = 0.002). The SOD activity decreased after 30 days, regardless of group (p < 0.001), which was maintained after 60 days. In Group A, there was a reduction in sulfhydryl levels at 60 days (p < 0.001). It is important to highlight that both groups demonstrated efficacy in the clinical improvement of melasma within at least 60 days, reducing the MASI score by almost 50%. However, microneedling with retinoic acid seems to be the worst treatment because there is a reduction in the non-enzymatic antioxidant defense, which is important to protect against oxidative stress.

The impact of red grape juice (Vitis labrusca)consumption associated with physical training on oxidative stress, inflammatory and epigenetic modulation in healthy elderly women.

The imbalance of epigenetic, oxidative stress and inflammatory markers is associated with the aging physiopathology. Then, the influence of bioactive nutritional compounds and physical training on these biomarkers has been studied, although the combination of both strategies has been not investigated. Therefore, our aim was to verify the effect of the association of physical training with red grape juice (Vitis labrusca) consumption on global histone acetylation H3 and H4 levels, oxidative stress markers and interleukin 6 (IL-6) levels in peripheral blood of healthy elderly women. This double-blind randomized clinical study consisted of 29 volunteers, aged 59 years and over, divided into three groups: grape juice group (GJG, n = 9); placebo and exercise group (PLEG, n = 10) and grape juice and exercise group (GJEG, n = 10). During 1 month, GJG consumed 400 ml of grape juice per day (integral and conventional), while the PLEG and GJEG groups, besides consuming juice or placebo were submitted to a concurrent physical training protocol (two times per week, 60 min / session). The volunteers were submitted to blood collections before and after the intervention for the biomarkers analysis, e.g. IL-6, histone acetylation H3 and H4, lipid oxidative damage (TBARS), proteins (Carbonyl), non-enzymatic antioxidant defense (Sulfhydryl groups) and activity of antioxidant enzymes (superoxide dismutase and catalase). There were no statistically significant differences in the global levels of histone acetylation H3 and H4 post intervention compared to the basal period as well and between groups were found. However, PLEG and GJEG showed a remarkable reduction on IL-6 levels after intervention. We also observed an increase in Carbonyl levels, SOD activities and Sulfhydryl levels comparing before and after intervention. Considering the interaction of time and groups, a significant increase in Sulfhydryl levels only in GJG was found. The physical training protocol associated or not with grape juice consumption showed anti-inflammatory effects and an influence in the antioxidant defenses (non enzymatic and enzymatic) in elderly women. However in grape juice group, without exercise, we observed an increase in non enzymatic antioxidant defense, what could be attributed to the polyphenols content. These responses seem not to be involved with histone acetylation status.

Kinesiotherapy With Exergaming as a Potential Modulator of Epigenetic Marks and Clinical Functional Variables of Older Women: Protocol for a Mixed Methods Study.

BACKGROUND: Kinesiotherapy is an option to mitigate worsening neuropsychomotor function due to human aging. Moreover, exergames are beneficial for the practice of physical therapy by older patients. Physical exercise interventions are known to alter the epigenome, but little is known about their association with exergames. OBJECTIVE: We aim to evaluate the effects of kinesiotherapy with exergaming on older women's epigenetic marks and cognitive ability, as well as on their clinical functional variables. Our hypothesis states that this kind of therapy can elicit equal or even better outcomes than conventional therapy. METHODS: We will develop a virtual clinic exergame with 8 types of kinesiotherapy exercises. Afterward, we will conduct a 1:1 randomized clinical trial to compare the practice of kinesiotherapy with exergames (intervention group) against conventional kinesiotherapy (control group). A total of 24 older women will be enrolled for 1-hour sessions performed twice a week, for 6 weeks, totaling 12 sessions. We will assess outcomes using epigenetic blood tests, the Montreal Cognitive Assessment test, the Timed Up and Go test, muscle strength grading in a hydraulic dynamometer, and the Game Experience Questionnaire at various stages. RESULTS: The project was funded in October 2019. Game development took place in 2020. Patient recruitment and a clinical trial are planned for 2021. CONCLUSIONS: Research on this topic is likely to significantly expand the understanding of kinesiotherapy and the impact of exergames. To the best of our knowledge, this may be one of the first studies exploring epigenetic outcomes of exergaming interventions. TRIAL REGISTRATION: Brazilian Clinical Trials Registry/Registro Brasileiro de Ensaios Clínicos (ReBEC) RBR-9tdrmw; https://ensaiosclinicos.gov.br/rg/RBR-9tdrmw. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32729.

Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress.

Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P2X7 receptors (P2X7R) and adenosine A2A receptors (A2AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between P2X7R and A2AR. Adult rats exposed to restraint stress for 14 days displayed an anxious (thigmotaxis, elevated plus maze), depressive (anhedonia, increased immobility), and amnesic (modified Y maze, object displacement) profile, together with increased expression of Iba-1 (a marker of microglia "activation") and interleukin-1ß (IL1ß) and tumor necrosis factor α (TNFα; proinflammatory cytokines) and an up-regulation of P2X7R (mRNA) and A2AR (receptor binding) in the hippocampus and prefrontal cortex. All these features were attenuated by the P2X7R-preferring antagonist brilliant blue G (BBG, 45 mg/kg, i.p.) or by caffeine (0.3 g/L, p.o.), which affords neuroprotection through A2AR blockade. Notably, BBG attenuated A2AR upregulation and caffeine attenuated P2X7R upregulation. In microglial N9 cells, the P2X7R agonist BzATP (100 µM) or the A2AR agonist CGS26180 (100 nM) increased calcium levels, which was abrogated by the P2X7R antagonist JNJ47965567 (1 µM) and by the A2AR antagonist SCH58261 (50 nM), respectively; notably JNJ47965567 prevented the effect of CGS21680 and the effect of BzATP was attenuated by SCH58261 and increased by CGS21680. These results provide the first demonstration of a functional interaction between P2X7R and A2AR controlling microglia reactivity likely involved in behavioral adaptive responses to stress and are illustrative of a cooperation between the two arms of the purinergic system in the control of brain function.

Effects of a multimodal exercise protocol on functional outcomes, epigenetic modulation and brain-derived neurotrophic factor levels in institutionalized older adults: a quasi-experimental pilot study.

Epigenetic changes have been shown to be associated with both aging process and aging-related diseases. There is evidence regarding the benefits of physical activity on the functionality, cognition, and quality of life of institutionalized older adults, however, the molecular mechanisms involved are not elucidated. The purpose of this pilot study was to investigate the effects of a multimodal exercise intervention on functional outcomes, cognitive performance, quality of life (QOL), epigenetic markers and brain-derived neurotrophic factor (BDNF) levels among institutionalized older adult individuals. Participants (n = 8) without dementia who were aged 73.38 ± 11.28 years and predominantly female (87.5%) were included in this quasi-experimental pilot study. A multimodal exercise protocol (cardiovascular capacity, strength, balance/agility and flexibility, perception and cognition) consisted of twice weekly sessions (60 minutes each) over 8 weeks. Balance (Berg Scale), mobility (Timed Up and Go test), functional capacity (Six-Minute Walk test), cognitive function (Mini-Mental State Examination) and QOL (the World Health Organization Quality of Life-BREF Scale questionnaire) were evaluated before and after the intervention. Blood sample (15 mL) was also collected before and after intervention for analysis of biomarkers global histone H3 acetylation and brain-derived neurotrophic factor levels. Significant improvements were observed in cognitive function, balance, mobility, functional capacity and QOL after the intervention. In addition, a tendency toward an increase in global histone H3 acetylation levels was observed, while brain-derived neurotrophic factor level remained unchanged. This study provided evidence that an 8-week multimodal exercise protocol has a significant effect on ameliorating functional outcomes and QOL in institutionalized older adult individuals. In addition, it was also able to promote cognitive improvement, which seems to be partially related to histone hyperacetylation status. The Ethics Research Committee of Centro Universitário Metodista-IPA, Brazil approved the current study on June 6, 2019 (approval No. 3.376.078).

Aquatic exercise associated or not with grape juice consumption-modulated oxidative parameters in Parkinson disease patients: A randomized intervention study.

Parkinson's disease (PD) is a neurodegenerative disorder with significant motor disabilities and cognitive decline. Importantly, the imbalance of oxidative stress is related to PD physiopathology and progression. This study aimed to evaluate the impact of grape juice consumption associated with an aquatic exercise protocol on oxidative stress parameters and cognitive function in individuals with PD. The participants were randomized into two groups: grape juice group (GJG) and control group (CG) and were submitted to 4 weeks of an aquatic intervention (twice a week, approximately 60 minutes/session). The GJG also consumed 400 ml of grape juice per day (integral and conventional) during this period. Cognitive function was assessed by the Montreal Cognitive Assessment (MoCa) questionnaire. For the analysis of oxidative stress markers, specifically lipid oxidative damage (TBARS), proteins (Carbonil), acid uric and the activity of antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase), blood collection were done before and after intervention. No changes were observed in cognitive function after intervention in both groups. Regarding biomarkers, a reduction of antioxidant enzymes, thiobarbituric acid reactive substances (TBARS) and uric acid was observed in both groups. However, only the GJG showed a significant reduction on protein oxidation levels after intervention. In conclusion, the consumption of grape juice associated with an aquatic exercise protocol might be consider an effective alternative to reduce the oxidative damage in PD, reinforcing the importance of this intervention in promoting beneficial impact in this population.

Therapeutic effectiveness of a single exercise session combined with WalkAide functional electrical stimulation in post-stroke patients: a crossover design study.

A growing body of evidence has suggested that the imbalance of epigenetic markers and oxidative stress appears to be involved in the pathophysiology and progression of stroke. Thus, strategies that modulate these biomarkers might be considered targets for neuroprotection and novel therapeutic opportunities for these patients. Physical exercise has been reported to induce changes in these epigenetic markers and improve clinical outcomes in different populations. However, little is reported on this in post-stroke patients. The purpose of this study was to investigate the effect of a single exercise session with WalkAide functional electrical stimulation (FES) on cognitive performance, clinical functional parameters, oxidative stress and epigenetic modulation in post-stroke individuals. In this crossover design study, 12 post-stroke individuals aged 54-72 years of either sexes were included and subjected to a single session of exercise (45 minutes) without WalkAide functional electrical stimulation (EXE alone group), followed by another single session of exercise (45 minutes) with WalkAide functional electrical stimulation (EXE + FES group). The clinical functional outcome measures, cognitive performance and blood collections for biomarker measurements were assessed pre- and post-intervention. After intervention, higher Berg Balance Scale scores were obtained in the EXE + FES group than in the EXE alone group. There was no significant difference in the Timed Up and Go test results post-intervention between EXE alone and EXE + FES groups. After intervention, a better cognitive performance was found in both groups compared with before the intervention. After intervention, the Timed Up and Go test scores were higher in the EXE + FES group than in the EXE alone group. In addition, the intervention induced lower levels of lipid peroxidation. After intervention, carbonyl level was lower, superoxide dismutase activity and superoxide dismutase/catalase activity ratio were higher in the EXE + FES group, compared with the EXE group alone. In each group, both histone deacetylase (HDAC2) and histone acetyltransferase activities were increased after intervention compared with before the intervention. These findings suggest that a single exercise session with WalkAide FES is more effective on balance ability and cognitive performance compared with conventional exercise alone in post-stroke patients. This is likely to be related to the regulation of oxidative stress markers. The present study was approved by the Research Ethics Committee of the Methodist University Center-IPA (approval No. 2.423.376) on December 7, 2017 and registered in the Brazilian Registry of Clinical Trials-ReBEC (RBR-9phj2q) on February 11, 2019.

The effect of consumption of purple grape juice in the gestational period on oxidative stress parameters in Wistar rat foetuses.

This study aimed to evaluate the effects of purple grape juice consumption in pregnancy on oxidative stress parameters in Wistar rat fetuses. Twenty-four pregnant rats were divided into five groups: control group, indomethacin group (received a single dose of indomethacin in DG20), group grape juice DG14 (received an amount for 14 days/first and second gestational trim), group grape juice DG20 (received a dose throughout the gestational period), group grape juice two doses (received two doses, at morning and afternoon). On the 20th day of pregnancy (DG20), rats were anesthetized, and a cesarean section was performed to obtain the fetuses. A sample of liver, heart, and total brain of fetuses was collected for oxidative stress analyses. Values P<0.05 were considered significant. In fetuses' heart, we observed that the grape juice two dose group decreased sulfhydryl and increased SOD. In the liver, the grape juice decreased TBARS and SOD. There was a decrease in carbonyl and sulfhydryl in the indomethacin and grape juice one dose groups in the brain. We conclude that indomethacin altered oxidative stress parameters only in the fetal brain, and grape juice was presented as an important modulator of antioxidant capacity when consumed in a dose.

Effect of exercise and grape juice on epigenetic modulation and functional outcomes in PD: A randomized clinical trial.

OBJECTIVE: This study aimed to investigate the impact of an aquatic physical training program associated with grape juice (Vitis labrusca) consumption on functional outcomes, Brain-Derived Neurotrophic Factor (BDNF) and global histone H4 acetylation levels in peripheral blood from individuals with Parkinson's disease. METHODS: Nineteen participants were randomized to Aquatic Exercise (AQ, n = 9) and Aquatic Exercise + Grape Juice (AQ+GJ, n = 10) groups and performed to 4 weeks of an aquatic intervention (twice a week, approximately 60 min/session). The AQ+GJ groups also consumed 400 mL of grape juice per day during this period. Functional capacity (six-min walk test, 6MWT), mobility (The Timed Up and Go, TUG) and the risk of falls (Berg Balance Scale, BBS) were evaluated before and after intervention. In addition, blood collections were carried out for biomarker analysis (e.g. BDNF and global histone H4). RESULTS: The aquatic exercise program induced functional improvement in individuals with Parkinson's disease, specifically ameliorating their mobility and functional capacity. In addition, enhanced levels of BDNF and histone H4 acetylation were found after the intervention. Grape juice consumption did not potentiate these effects, since any significant differences between the AQ and AQ+GJ groups were not found in all analysed variables. CONCLUSIONS: The present study provides important insights about aquatic exercise-modulated BDNF levels in individuals with Parkinson's disease in combination with functional improvements, suggesting that histone acetylation status may interact to dictate the molecular mechanisms involved in this response. Parkinson disease, aquatic exercise, BDNF, epigenetic, grape juice.

Aquatic exercise program-modulated oxidative stress markers in patients with Parkinson's disease.

Parkinson's disease is a neurodegenerative disease. Oxidative stress, i.e., the imbalance between the generation of reactive oxygen species and the antioxidant defense capacity of the body, plays an important role in the pathogenesis of this disease. Physical exercise can regulate oxidative stress. The purpose of this study was to analyze the short- and long-term effects of an aquatic exercise program on oxidative stress levels in patients with Parkinson's disease. The aquatic exercise program was carried out during 1 month with two sessions per week (1 hour/session). Blood samples were collected at four different time points: pre-intervention, immediately, 48 hours, and 30 days after the first session of aquatic exercise program. Our results revealed that water-based programs modulated antioxidant enzyme activity, increased superoxide dismutase activity, reduced catalase activity, and increased the ratio of superoxide dismutase activity to catalase activity in patients with Parkinson's disease. Compared with pre-intervention and 48 hours after the first session of aquatic exercise program, superoxide dismutase activity was higher and catalase activity was lower immediately and 30 days after the first session. Our results demonstrated that aquatic exercise program could modulate oxidative stress, mainly by the effect of antioxidant enzyme activity. These results could better help understand the target of oxidative stress in Parkinson's disease. This study was approved by the Ethics Committee of Centro Universitário Metodista IPA (approval No. 1.373.911) on August 9, 2019 and registered with REBEC (registration number: RBR-6NJ4MK).

Effects of grape juice consumption on oxidative stress and inflammation in male volleyball players: A randomized, double-blind, placebo-controlled clinical trial.

INTRODUCTION: Some foods are also demonstrated benefits, such as anti-inflammatory, antioxidant, and ergogenic activity, similar to that of sports supplements. Grape juice has been considered an important source of polyphenols and these compounds could promote positive effects to the sports players. In this sense, the objective was to evaluate the effects of purple grape juice consumption on indicators of oxidative stress, inflammation, muscle damage, global histone H4 acetylation levels, and muscle strength and muscle power in volleyball athletes. METHODS: This is a randomized double-blind clinical trial in which 12 male volleyball players (16 ± 0.6 years old) participated in three different moments with match simulation: control (without beverage) (WB), grape juice (GJ) and placebo (PLA) (400 mL/day of grape juice or placebo (maltodextrin) for 14 days in a cross-over model). Before and immediately after each match, blood collection for analysis of indicators of systemic redox status, systemic concentrations of Interferon-γ (IFN- γ) and Interleukin-4 (IL-4), muscle damage, by Creatine Kinase (CK-NAC) and levels of global histone H4 acetylation were performed, as well as handgrip strength (HG) and lower limb power tests. RESULTS: Consumption of grape juice significantly reduced lipid peroxidation (p = 0.04) and Deoxyribonucleic Acid (DNA) damage (p = 0.01) after the match. IFN-γ levels, IL-4, CK-NAC, and histone H4 acetylation post-match did not alter with the grape juice consumption. Lower limb power improved after acute exercise in WB and GJ conditions (p < 0.001). CONCLUSION: In this pilot trial, the intake of grape juice for two weeks seems to reduce the protein oxidation and DNA damage by intermittent physical exercise, without epigenetics influence.

Inosine prevents hyperlocomotion in a ketamine-induced model of mania in rats.

Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A1 and A2A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A1 and A2A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats.

Does a single bout of exercise impacts BDNF, oxidative stress and epigenetic markers in spinal cord injury patients?

Our aim was to evaluate the impact of a single bout of exercise, consisting of a gait training session with body weight support (BWS), on histone acetylation status (global histone H4 and H3 acetylation levels), brain-derived neurotrophic factor (BDNF) levels, and oxidative stress markers in peripheral blood of individuals with chronic spinal cord injury (SCI). We also set out to compare these responses with those recorded after gait training performed using a walker and with no BWS. The subjects (nearly all with an incomplete spinal cord lesion) were each submitted to two 60-minute experimental sessions on separate days with a 1- week wash-out period between the interventions. The order of the sessions was randomized. Blood samples were collected before and after each experimental trial for measurement of biomarkers. The histone acetylation status and BDNF levels remained unchanged after both interventions. After the treadmill training, the participants showed a strong increase in levels of oxidative stress markers [plasma advanced oxidation protein products (AOPPs), nitrite and thiobarbituric acid-reactive substances] without changes in antioxidant mediators. Instead, elevations in AOPP and nitrite concentrations, in addition to increased levels of glutathione and catalase activity, were found after the walker training. A single bout of gait training, be it conducted on a treadmill with BWS or using a walker without BWS, is not able to alter BDNF levels and histone acetylation status in SCI patients. However, these trials can modulate oxidative stress parameters, seemingly in a protocol-dependent manner.

The impact of an aquatic exercise program on BDNF levels in Parkinson's disease patients: short-and long-term outcomes.

The present study aimed to analyze the short-and long-term effects of an aquatic exercise program on plasma brain-derived neurotrophic factor (BDNF) levels in individuals with Parkinson's disease (PD). The aquatic exercise program lasted one month, and consisted of two sessions per week (1 hour per session). Blood samples were collected at four different timepoints: pre-intervention (T0), immediately after the first session (T1), 48 hours after the first session (T2), and 1 month after the intervention (T3). We found a significant decrease in BDNF levels at T2 vs T1 (p<0.05). However, no changes were observed at the other time-points. Our results demonstrated that the intervention reduced plasma BDNF levels in PD individuals in a time-dependent manner: specifically, we observed acute effects, but no delayed effects.