Viviane Rostirola Elsner

Treadmill exercise induces age-related changes in aversive memory, neuroinflammatory and epigenetic processes in the rat hippocampus.

It has been described that exercise can modulate both inflammatory response and epigenetic modifications, although the effect of exercise on these parameters during the normal brain aging process yet remains poorly understood. Here, we investigated the effect of aging and treadmill exercise on inflammatory and epigenetic parameters specifically pro and anti-inflammatory cytokines levels, activation of NF-kB and histone H4 acetylation levels in hippocampus from Wistar rats. Additionally, we evaluated aversive memory through inhibitory avoidance task. Rats of 3 and 20 months of age were assigned to non-exercised (sedentary) and exercised (running daily for 20 min for 2 weeks) groups. The effect of daily forced exercise in the treadmill was assessed. The levels of inflammatory and epigenetic parameters were determined 1h, 18 h, 3 days or 7 days after the last training session of exercise. It was observed an age-related decline on aversive memory, as well as aged rats showed increased hippocampal levels of inflammatory markers, such as TNFα, IL1-β and NF-kB and decreased IL-4 levels, an anti-inflammatory cytokine. Moreover, lower levels of global histone H4 acetylation were also observed in hippocampi from aged rats. Interestingly, there was a significant correlation between the biochemical markers and the inhibitory avoidance test performance. The forced exercise protocol ameliorated aging-related memory decline, decreased pro-inflammatory markers and increased histone H4 acetylation levels in hippocampi 20-months-old rats, while increased acutely IL-4 levels in hippocampi from young adult rats. Together, these results suggest that an imbalance of inflammatory markers might be involved to the aging-related aversive memory impairment. Additionally, our exercise protocol may reverse aging-related memory decline through improving cytokine profile.

Exercise induces age-dependent changes on epigenetic parameters in rat hippocampus: a preliminary study.

Regular exercise improves learning and memory, including during aging process. Interestingly, the imbalance of epigenetic mechanisms has been linked to age-related cognitive deficits. However, studies about epigenetic alterations after exercise during the aging process are rare. In this preliminary study we investigated the effect of aging and exercise on DNA methyltransferases (DNMT1 and DNMT3b) and H3-K9 methylation levels in hippocampus from 3 and 20-months aged Wistar rats. The animals were submitted to two exercise protocols: single session or chronic treadmill protocol. DNMT1 and H3-K9 methylation levels were decreased in hippocampus from aged rats. The single exercise session decreased both DNMT3b and DNMT1 levels in young adult rats, without any effect in the aged group. Both exercise protocols reduced H3-K9 methylation levels in young adult rats, while the single session reversed the changes on H3-K9 methylation levels induced by aging. Together, these results suggest that an imbalance on DNMTs and H3-K9 methylation levels might be linked to the brain aging process and that the outcome to exercise seems to vary through lifespan.

Exposition to tannery wastewater did not alter behavioral and biochemical parameters in Wistar rats.

There are scarce data on the neurotoxicity in mammalian induced by tannery wastewaters. Previously, the anxiogenic effect of tannery wastewater was demonstrated in mice, while wastewater submitted to photoelectrooxidation (PEO) process treatment did not affect the anxiety state. Considering that species may response differently to xenobiotics, the aim of the present work was to study the effects of exposure to tannery wastewaters (non-PEO or PEO-treated) on behavioral and neurochemical markers in another species of laboratory animals, specifically Wistar rats. Male Wistar rats were given free access to water bottles containing non-PEO or PEO-treated tannery wastewaters (0.1, 1 and 5% in drinking water). During the exposure, behavioral tests of anxiety (elevated plus-maze, neophobia, open field and light-dark box), depression (forced swimming) and memory (inhibitory avoidance, novel object and discriminative avoidance) were performed. On the 30th day, brain structures were dissected out to evaluate cellular oxidative state (hippocampus, cerebellum and striatum) and acetylcholinesterase activity (hippocampus and striatum). Exposure to tannery effluent with or without photoelectrochemical treatment did not alter any behavioral and neurochemical parameters evaluated. Our data indicate that Wistar rats may not be an adequate species for ecotoxicological studies involving tannery effluents and that POE treatment did not generate other toxic compounds.

Histone deacetylase activity is altered in brain areas from aged rats.

It has been described that histone acetylation levels are decreased in several cellular and in vivo neurodegeneration models as well as in normal brain aging, although the impact of the aging process on histone deacetylases (HDAC) activity yet remains poorly understood. Therefore, our aim was to evaluate the effect of the aging process on HDAC activity in hippocampi and frontal cortices from 3 and 18-months-old Wistar rats. The animals were decapitated at different times of day, in the early morning and in afternoon. HDAC activity was increased in hippocampus from the aged group. Besides, the hippocampal HDAC activity was also significantly increased in early morning. A significant interaction between age and time of the day was observed in frontal cortices, given that the HDAC activity was higher in early morning in the aged group. These data support the hypothesis that the aging-related dysfunction may be related, at least in part, to acetylation imbalance through HDAC activity in rat brain.

Time-dependent effects of treadmill exercise on aversive memory and cyclooxygenase pathway function

Exercise induces brain function adaptations and improves learning and memory; however the time window of exercise effects has been poorly investigated. Studies demonstrate an important role for cyclooxygenase-2 (COX-2) pathway function in the mechanisms underlying memory formation. The aim of present work was to investigate the effects of treadmill exercise on aversive memory and COX-2, PGE(2) and E-prostanoid receptors contents in the rat hippocampus at different time points after exercise has ended. Adult male Wistar rats were assigned to non-exercised (sedentary) and exercised (running daily for 20min, for 2weeks) groups. The inhibitory avoidance task was used to assess aversive memory and the COX-2, PGE(2) and E-prostanoid receptors (EP1, EP2, EP3 and EP4) levels were determined 1h, 18h, 3days or 7days after the last training session of treadmill exercise. The step down latency in the inhibitory avoidance, COX-2 and EP4 receptors levels were acutely increased by exercise, with a significant positive correlation between aversive memory performance and COX-2 levels. Increased EP2 content decreased PGE(2) levels were observed 7days after the last running session. The treadmill exercise protocol facilitates inhibitory avoidance memory and induces time-dependent changes on COX-2 pathways function (COX-2, PGE(2) and EP receptors).

Exercise-induced modulation of histone H4 acetylation status and cytokines levels in patients with schizophrenia

The present study aimed to investigate the short and long-term effects of a concurrent exercise protocol on global histone H4 acetylation levels and inflammatory markers (interleukin-4 (IL-4), interleukin-6 (IL-6), interferon gamma (IFN-γ) and cortisol) in phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMC) and in peripheral blood of patients with schizophrenia (SZ), as well the intervention impact on anthropometric characteristics. Seventeen individuals were submitted to the intervention three times a week and blood samples were collected pre, 30, 60 and 90days after the intervention started. A remarkable reduction on body mass index and body mass were observed following intervention. The protocol also induced a histone H4 hypoacetylation status in PBMC all times evaluated when compared to the pre intervention period. Although the IL-4 and cortisol levels were not altered in response to the intervention, a reduction in IL-6 production during the 60 and 90days compared to the pre intervention period was observed. Finally, diminished IFN-γ production was found in the 90days period compared to the pre intervention and 30days after periods. In addition, systemic IL-6 levels were lower at 60 and 90days compared to the pre intervention. The concurrent exercise protocol was able to improve anthropometric characteristics in patients with SZ, engaging the modulation of cytokine and histone H4 acetylation levels.

Exercise-modulated epigenetic markers and inflammatory response in COPD individuals: A pilot study

The study investigated the effects of exercise on epigenetic signals and systemic cytokine levels in chronic obstructive pulmonary disease (COPD) individuals. Ten participants of a pulmonary rehabilitation program were submitted to 24 sessions of a supervisioned exercise protocol thrice-weekly (90min/session). Blood samples were collected at baseline, after the 1st session, before and after the 24th session. A DNA hypomethylation status was observed after the 1st session when compared at baseline, while global histone H4 acetylation status was unaltered in any time-points evaluated. No significant changes were observed on cytokine levels after the 1st session. A significant enhancement on interleukin 6 (IL-6) and a decrease on transforming growth factor-beta (TGF-β) levels were found after the 24th session when compared to the pre 24th session. Moreover, 23 sessions of exercise were able to diminish significantly the basal levels of IL-6 and interleukin 8 (IL-8). These data suggest a potential role of epigenetic machinery in mediating the anti-inflammatory effects of exercise in COPD patients.

Acute Strenuous Exercise Induces an Imbalance on Histone H4 Acetylation/Histone Deacetylase 2 and Increases the Proinflammatory Profile of PBMC of Obese Individuals

This study evaluated the response of global histone H4 acetylation (H4ac), histone deacetylase 2 (HDAC2) activity, as well as the production of proinflammatory cytokines and monocyte phenotypes of lean and obese males after exercise. Ten lean and ten obese sedentary men were submitted to one session of strenuous exercise, and peripheral blood mononuclear cells (PBMC) were stimulated in vitro with lipopolysaccharide (LPS). Global H4ac levels, HDAC2 activity in PBMC, and IL-6, IL-8, and TNF-α production were analyzed. Monocyte phenotype was determined in accordance with the expression of CD14 and CD16. At rest, obese individuals presented higher frequency of proinflammatory CD14+CD16+ monocytes. LPS induced a significant augment in global H4ac and in the production of IL-6, IL-8, and TNF-α mainly in obese individuals. After exercise, the increased production of IL-8 and TNF-α and peripheral frequency of CD14+CD16+ were observed in both groups. In addition, exercise also induced a significant hyperacetylation of histone H4 and decreased HDAC2 activity in both nonstimulated and LPS-stimulated PBMC of obese individuals. Our data indicate that the obesity impacts on H4ac levels and that strenuous exercise leads to an enhanced chronic low-grade inflammation profile in obesity via an imbalance on H4ac/HDAC2.

Treadmill exercise alters histone acetylation differently in rats exposed or not exposed to aversive learning context

Epigenetic modifications have been linked to memory formation after learning context exposure and to exercise effects on memory performance. The aim of this study was to investigate the effect of treadmill exercise (20 min/day during 2 weeks) on H3K14 acetylation and H3S10 phosphorylation levels in the hippocampi of 3-month-old Wistar rats exposed and not exposed to aversive learning context. Male Wistar rats aged 2-3 months were assigned to non-exercised (sedentary) and exercised (running daily for 20 min for 2 weeks) groups. Single-trial step-down inhibitory avoidance (IA) conditioning was employed as an aversive memory model. Epigenetic parameters were determined 30 min after the IA test. A decrease in the H3K14 acetylation in the hippocampus 24 h after IA training (30 min after test session) was observed. Exercise reversed the IA effect, and no effect was observed in the non-IA exposed group. Our data support the hypothesis that modulation of H3K14 acetylation levels in the hippocampus might be related, at least in part, to exercise effects on aversive memory.

Effect of tannery effluent on oxidative status of brain structures and liver of rodents

Oxidative stress has been considered as a central mechanism of toxicity induced by xenobiotics. Previously, it was demonstrated that mice exposed to tannery effluent showed an anxiety-like behavior, without any comparable behavioral effects in rats. The aim of the present study was to investigate the impact of tannery wastewater on oxidative status in in vitro and in vivo assays with two mammal species, mice and rats. Specifically, homogenates of two brain areas and the liver were incubated with tannery wastewater; reactive species and lipid peroxidation levels and antioxidant enzyme activities were detected. In addition, the effects of in vivo exposure of mice to tannery effluents on and lipid peroxidation levels and the total reactive antioxidant capacity in brain areas and liver. Brain areas, the hippocampus and frontal cortex, and the liver of mice exposed to tannery wastewater showed oxidative stress. Our data suggest that divergent species-dependent hepatic enzymes adaptations, such as glutathione peroxidase and glutathione S-transferase activities, induced by tannery effluent could explain previous behavioral findings.