Caffeine improves mitochondrial function in PINK1B9-null mutant Drosophila melanogaster.

Mitochondrial dysfunction plays a central role in Parkinson's disease (PD) and can be triggered by xenobiotics and mutations in mitochondrial quality control genes, such as the PINK1 gene. Caffeine has been proposed as a secondary treatment to relieve PD symptoms mainly by its antagonistic effects on adenosine receptors (ARs). Nonetheless, the potential protective effects of caffeine on mitochondrial dysfunction could be a strategy in PD treatment but need further investigation. In this study, we used high-resolution respirometry (HRR) to test caffeine's effects on mitochondrial dysfunction in PINK1B9-null mutants of Drosophila melanogaster. PINK1 loss-of-function induced mitochondrial dysfunction in PINK1B9-null flies observed by a decrease in O2 flux related to oxidative phosphorylation (OXPHOS) and electron transfer system (ETS), respiratory control ratio (RCR) and ATP synthesis compared to control flies. Caffeine treatment improved OXPHOS and ETS in PINKB9-null mutant flies, increasing the mitochondrial O2 flux compared to untreated PINKB9-null mutant flies. Moreover, caffeine treatment increased O2 flux coupled to ATP synthesis and mitochondrial respiratory control ratio (RCR) in PINK 1B9-null mutant flies. The effects of caffeine on respiratory parameters were abolished by rotenone co-treatment, suggesting that caffeine exerts its beneficial effects mainly by stimulating the mitochondrial complex I (CI). In conclusion, we demonstrate that caffeine may improve mitochondrial function by increasing mitochondrial OXPHOS and ETS respiration in the PD model using PINK1 loss-of-function mutant flies.

Neuromodulation and neuroprotective effects of chlorogenic acids in excitatory synapses of mouse hippocampal slices.

The increased healthspan afforded by coffee intake provides novel opportunities to identify new therapeutic strategies. Caffeine has been proposed to afford benefits through adenosine A2A receptors, which can control synaptic dysfunction underlying some brain disease. However, decaffeinated coffee and other main components of coffee such as chlorogenic acids, also attenuate brain dysfunction, although it is unknown if they control synaptic function. We now used electrophysiological recordings in mouse hippocampal slices to test if realistic concentrations of chlorogenic acids directly affect synaptic transmission and plasticity. 3-(3,4-dihydroxycinnamoyl)quinic acid (CA, 1-10 µM) and 5-O-(trans-3,4-dihydroxycinnamoyl)-D-quinic acid (NCA, 1-10 µM) were devoid of effect on synaptic transmission, paired-pulse facilitation or long-term potentiation (LTP) and long-term depression (LTD) in Schaffer collaterals-CA1 pyramidal synapses. However, CA and NCA increased the recovery of synaptic transmission upon re-oxygenation following 7 min of oxygen/glucose deprivation, an in vitro ischemia model. Also, CA and NCA attenuated the shift of LTD into LTP observed in hippocampal slices from animals with hippocampal-dependent memory deterioration after exposure to ß-amyloid 1-42 (2 nmol, icv), in the context of Alzheimer's disease. These findings show that chlorogenic acids do not directly affect synaptic transmission and plasticity but can indirectly affect other cellular targets to correct synaptic dysfunction. Unraveling the molecular mechanisms of action of chlorogenic acids will allow the design of hitherto unrecognized novel neuroprotective strategies.

A1 rather than A2A adenosine receptor as a possible target of Guanosine effects on mitochondrial dysfunction following Traumatic Brain Injury in rats.

Traumatic brain injury (TBI) represents one of the leading causes of death worldwide. Its pathophysiology involves several neurochemical events including mitochondrial dysfunction. Since mitochondrial respiration plays a key role in cell survival, pharmacological interventions targeting mitochondrial function have been highlighted as a powerful tool against the neurodegenerative process triggered by TBI. Guanosine (GUO), a neuroprotective molecule in different neurological disorders involving neurotoxicity, has shown protective properties after TBI, however its mechanism of action is not well understood in the central nervous system (CNS). Therefore, the aim of this study is to evaluate the possible target receptor involved in the protective GUO effects on TBI-induced mitochondrial dysfunction in the cerebral cortex of rats. Results show that a single dose of GUO (7.5 mg/kg) injected 40 min after a fluid percussion injury (FPI) protects against loss of mitochondrial membrane potential and increase of reactive oxygen species 8 h post-TBI. These effects were specifically blocked by a pretreatment (10 min after TBI) with an A1 adenosine receptor antagonist (DPCPX 1 mg/kg). In contrast, pretreatment with an A2A adenosine receptor antagonist (SCH 58261 0.05 mg/kg) did not alter GUO effects. These findings suggest that acute GUO neuroprotection following TBI involves the modulation of the adenosinergic system, especially A1 adenosine receptor.

Guanosine Attenuates Behavioral Deficits After Traumatic Brain Injury by Modulation of Adenosinergic Receptors.

Traumatic brain injury (TBI) is a leading cause of disability worldwide, triggering chronic neurodegeneration underlying cognitive and mood disorder still without therapeutic prospects. Based on our previous observations that guanosine (GUO) attenuates short-term neurochemical alterations caused by TBI, this study investigated the effects of chronical GUO treatment in behavioral, molecular, and morphological disturbances 21 days after trauma. Rats subject to TBI displayed mood (anxiety-like) and memory dysfunction. This was accompanied by a decreased expression of both synaptic (synaptophysin) and plasticity proteins (BDNF and CREB), a loss of cresyl violet-stained neurons, and increased astrogliosis and microgliosis in the hippocampus. Notably, chronic GUO treatment (7.5 mg/kg i.p. daily starting 1 h after TBI) prevented all these TBI-induced long-term behavioral, neurochemical, and morphological modifications. This neuroprotective effect of GUO was abrogated in the presence of the adenosine A1 receptor antagonist DPCPX (1 mg/kg) but unaltered by the adenosine A2A receptor antagonist SCH58261 (0.05 mg/kg). These findings show that a chronic GUO treatment prevents the long-term mood and memory dysfunction triggered by TBI, which involves adenosinergic receptors.

Sex-Specific Response of Caenorhabditis elegans to Methylmercury Toxicity.

Methylmercury (MeHg), an abundant environmental pollutant, has long been known to adversely affect neurodevelopment in both animals and humans. Several reports from epidemiological studies, as well as experimental data indicate sex-specific susceptibility to this neurotoxicant; however, the molecular bases of this process are still not clear. In the present study, we used Caenorhabditis elegans (C. elegans), to investigate sex differences in response to MeHg toxicity during development. Worms at different developmental stage (L1, L4, and adult) were treated with MeHg for 1 h. Lethality assays revealed that male worms exhibited significantly higher resistance to MeHg than hermaphrodites, when at L4 stage or adults. However, the number of worms with degenerated neurons was unaffected by MeHg, both in males and hermaphrodites. Lower susceptibility of males was not related to changes in mercury (Hg) accumulation, which was analogous for both wild-type (wt) and male-rich him-8 strain. Total glutathione (GSH) levels decreased upon MeHg in him-8, but not in wt. Moreover, the sex-dependent response of the cytoplasmic thioredoxin system was observed-males exhibited significantly higher expression of thioredoxin TRX-1, and thioredoxin reductase TRXR-1 expression was downregulated upon MeHg treatment only in hermaphrodites. These outcomes indicate that the redox status is an important contributor to sex-specific sensitivity to MeHg in C. elegans.

Brain infusion of α-synuclein oligomers induces motor and non-motor Parkinson's disease-like symptoms in mice.

Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of α-synuclein (α-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of α-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of α-syn oligomers (α-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that α-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45days post-infusion (dpi). α- SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of α-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantia nigra of α-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of α-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, α-SYOs i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to α-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening.

The Impact of Previous Physical Training on Redox Signaling after Traumatic Brain Injury in Rats: A Behavioral and Neurochemical Approach.

Throughout the world, traumatic brain injury (TBI) is one of the major causes of disability, which can include deficits in motor function and memory, as well as acquired epilepsy. Although some studies have shown the beneficial effects of physical exercise after TBI, the prophylactic effects are poorly understood. In the current study, we demonstrated that TBI induced by fluid percussion injury (FPI) in adult male Wistar rats caused early motor impairment (24 h), learning deficit (15 days), spontaneous epileptiform events (SEE), and hilar cell loss in the hippocampus (35 days) after TBI. The hippocampal alterations in the redox status, which were characterized by dichlorofluorescein diacetate oxidation and superoxide dismutase (SOD) activity inhibition, led to the impairment of protein function (Na(+), K(+)-adenosine triphosphatase [ATPase] activity inhibition) and glutamate uptake inhibition 24 h after neuronal injury. The molecular adaptations elicited by previous swim training protected against the glutamate uptake inhibition, oxidative stress, and inhibition of selected targets for free radicals (e.g., Na(+), K(+)-ATPase) 24 h after neuronal injury. Our data indicate that this protocol of exercise protected against FPI-induced motor impairment, learning deficits, and SEE. In addition, the enhancement of the hippocampal phosphorylated nuclear factor erythroid 2-related factor (P-Nrf2)/Nrf2, heat shock protein 70, and brain-derived neurotrophic factor immune content in the trained injured rats suggests that protein expression modulation associated with an antioxidant defense elicited by previous physical exercise can prevent toxicity induced by TBI, which is characterized by cell loss in the dentate gyrus hilus at 35 days after TBI. Therefore, this report suggests that previous physical exercise can decrease lesion progression in this model of brain damage.

Homeostatic effect of p-chloro-diphenyl diselenide on glucose metabolism and mitochondrial function alterations induced by monosodium glutamate administration to rats.

The metabolic syndrome is a group of metabolic alterations considered a worldwide public health problem. Organic selenium compounds have been reported to have many different pharmacological actions, such as anti-hypercholesterolemic and anti-hyperglycemic. The aim of this study was to evaluate the effect of p-chloro-diphenyl diselenide (p-ClPhSe)2, an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats. The rats were treated during the first ten postnatal days with MSG and received (p-ClPhSe)2 (10 mg/kg, intragastrically) from 45th to 51 th postnatal day. Glucose, lipid and lactate levels were determined in plasma of rats. Glycogen levels and activities of tyrosine aminotransferase, hexokinase, citrate synthase and glucose-6-phosphatase (G-6-Pase) were determined in livers of rats. Renal G-6-Pase activity was also determined. The purine content [Adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate] and mitochondrial functionality in the liver were also investigated. p-(ClPhSe)2 did not alter the reduction in growth performance and in the body weight caused by MSG but reduced epididymal fat deposition of rats. p-(ClPhSe)2 restored glycemia, triglycerides, cholesterol and lactate levels as well as the glucose metabolism altered in rats treated with MSG. p-(ClPhSe)2 restored hepatic mitochondrial dysfunction and the decrease in citrate synthase activity and ATP and ADP levels caused by MSG in rats. In summary, (p-ClPhSe)2 had homeostatic effects on glucose metabolism and mitochondrial function alterations induced by MSG administration to rats.

Changes in Purines Concentration in the Cerebrospinal Fluid of Pregnant Women Experiencing Pain During Active Labor.

Labor pain has been reported as a severe pain and can be considered as a model of acute visceral pain. It is well known that extracellular purines have an important role in pain signaling in the central nervous system. This study analyzes the relationship between extracellular purines and pain perception during active labor. A prospective observational study was performed. Cerebrospinal fluid (CSF) levels of the purines and their metabolites were compared between women at term pregnancy with labor pain (n = 49) and without labor pain (Caesarian section; n = 47). Control groups (healthy men and women without chronic or acute pain-n = 40 and 32, respectively) were also investigated. The CSF levels of adenosine were significantly lower in the labor pain group (P = 0.026) and negatively correlated with pain intensity measured by a visual analogue scale (r = -0.48, P = 0.0005). Interestingly, CSF levels of uric acid were significantly higher in healthy men as compared to women. Additionally, pregnant women showed increased CSF levels of ADP, GDP, adenosine and guanosine and reduced CSF levels of AMP, GTP, and uric acid as compared to non-pregnant women (P < 0.05). These findings suggest that purines, in special the nucleoside adenosine, are associated with pregnancy and labor pain.

Caffeine suppresses exercise-enhanced long-term and location memory in middle-aged rats: Involvement of hippocampal Akt and CREB signaling.

The cognitive function decline is closely related with brain changes generated by age. The ability of caffeine and exercise to prevent memory impairment has been reported in animal models and humans. The purpose of the present study was to investigate whether swimming exercise and caffeine administration enhance memory in middle-aged Wistar rats. Male Wistar rats (18months) received caffeine at a dose of 30mg/kg, 5days per week by a period of 4weeks. Animals were subjected to swimming training with a workload (3% of body weight, 20min per day for 4weeks). After 4weeks, the object recognition test (ORT) and the object location test (OLT) were performed. The results of this study demonstrated that caffeine suppressed exercise-enhanced long-term (ORT) and spatial (OLT) memory in middle-aged and this effect may be related to a decrease in hippocampal p-CREB signaling. This study also provided evidence that the effects of this protocol on memory were not accompanied by alterations in the levels of activated Akt. The [(3)H] glutamate uptake was reduced in hippocampus of rats administered with caffeine and submitted to swimming protocol.

Purple grape juice as a protector against acute x-irradiation induced alterations on mobility, anxiety, and feeding behaviour in mice.

The aim of this work was to test the hypothesis that a moderate intake of organic purple grape juice shows a positive radiomodifier effect over early behavioural damage following acute X-irradiation in mice. Anxiety-, locomotion-, and feeding-related responses to 6 Gy total body X-irradiation (TBI) were studied via open field, Rotarod, and feeding/drinking recording. Thirty-two male mice weighing 25-30 g were grouped according grape juice (J) or water (W) ad libitum drinking and either non-irradiated (N) or irradiated (R). 24 h post-TBI the access frequency to the center and corners of the open field was decreased, and the total stay in the corners increased, in RW vs. NW mice. Anxiety-related parameters decreased in RJ vs. RW mice. Rotarod latency times increased 72 h post-TBI in RJ vs RW mice. No overall changes in food and drink intake were observed along the experimental period. On the irradiation day, bout number was increased and bout duration was decreased in RW mice. The changes were reversed by purple grape juice intake. Grape juice intake before and after TBI can overcome several radiation-induced changes in behaviour within 24-72 hours after sub-lethal X-irradiation. This beneficial effect on short-term anxiety and mobilityrelated activities could probably be included in the list of flavonoid bio-effects. The present findings could be relevant in designing preventive interventions aimed to enhance body defense mechanisms against short-term irradiation damage.

El presente estudio tiene como objetivo comprobar la hipótesis de que una ingesta moderada de mosto ecológico de uva tinta presenta un efecto radiomodificador positivo sobre los daños comportamentales tempranos inducidos por la irradiación aguda con rayos X en el ratón. Se estudiaron respuestas relacionadas con el comportamiento ingestivo, ansiedad y locomoción frente a la irradiación aguda a cuerpo entero (TBI) con 6 Gy de rayos X, mediante registro directo de la ingestión de agua y alimento, rotarod y open field. Se utilizaron 32 ratones macho con un peso corporal entre 25 y 30 g, agrupados en función de haber sido sometidos a irradiación a cuerpo entero (R) o no (N) y de su ingesta de mosto (J) o agua (W) ad libitum. La frecuencia de acceso al centro y a las esquinas del open field disminuyó 24 horas después de la irradiación, mientras que aumentó la duración de la estancia en las esquinas en los ratones RW respecto a los NW. Los parámetros relacionados con ansiedad disminuyeron en ratones RJ respecto a los RW. No se observaron cambios significativos en la ingestión total de alimento y bebida durante los días analizados; sin embargo, en el día de la irradiación disminuyó el número total de episodios ingestivos al tiempo que aumentó el tamaño de los mismos. Estos cambios revirtieron en los animales que bebieron mosto. La ingesta de mosto antes y después de la irradiación puede revertir cambios comportamentales agudos inducidos por la irradiación subletal. El efecto beneficioso sobre la ansiedad y actividad motora a corto plazo podría ser relevante para diseñar intervenciones preventivas encaminadas a incrementar los mecanismos de defensa del cuerpo frente al daño por irradiación a corto plazo.

Moderate swimming exercise and caffeine supplementation reduce the levels of inflammatory cytokines without causing oxidative stress in tissues of middle-aged rats.

The levels of circulatory inflammatory markers, including interleukin (IL) IL-1ß, IL-6, tumor necrosis factor-α (TNF-α) and interferon (INF-γ), are known to increase associated to aging. Caffeine has been reported to produce many beneficial effects for health. Exercise is considered to be a safe medicine to attenuate inflammation and cellular senescence. The purpose of the present study was to investigate the effects of a moderate-intensity swimming exercise (3 % of body weight, 20 min per day, 4 weeks) and sub-chronic supplementation with caffeine (30 mg/kg, 4 weeks) on the serum cytokine levels in middle-aged (18 months) Wistar rats. The effects of swimming exercise and caffeine on oxidative stress in muscle and liver of middle-aged rats were also investigated. The two-way ANOVA of pro-inflammatory cytokine levels demonstrated a significant exercise x caffeine interaction for IL-1ß (F (1, 16) = 9.5772; p = 0.0069), IL-6 (F (1, 16) = 8.0463; p = 0.0119) and INF-γ (F (1, 16) = 15.078; p = 0.0013). The two-way ANOVA of TNF-α levels revealed a significant exercise × caffeine interaction (F (1, 16) = 9.6881; p = 0.00670). Swimming exercise and caffeine supplementation increased the ratio of reduced glutathione/oxidized glutathione in the rat liver and gastrocnemius muscle. Hepatic and renal markers of damage were not modified. In conclusion, a moderate-intensity swimming exercise protocol and caffeine supplementation induced positive adaptations in modulating cytokine levels without causing oxidative stress in muscle and liver of middle-aged rats.

New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.

The acute liver failure (ALF) induced by acetaminophen (APAP) is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe)2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe)2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe)2 to the N-acetylcysteine (NAC) during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg), (PhSe)2 (15.6 mg/kg), NAC (1200 mg/kg), APAP+(PhSe)2 or APAP+NAC, where the (PhSe)2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation) and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe)2. The effectiveness of (PhSe)2 was similar at a lower dose than NAC. In summary, (PhSe)2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.

Antioxidant effect of organic purple grape juice on exhaustive exercise.

This study aimed to assess the potential protective effect of organic purple grape juice (PGJ) on oxidative stress produced by an exhaustive exercise bout in rats. To test this hypothesis, rats were acutely treated with organic PGJ (Vitis labrusca) and subsequently submitted to an exhaustive exercise bout. Parameters of oxidative stress, such as thiobarbituric acid reactive species (TBARS) levels, 2',7',-dichlorofluorescein diacetate (DCFH-DA) oxidation, and nonprotein sulfhydryl levels (NP-SH) in the brain, skeletal muscle, and blood, were evaluated. Enzyme activity of Na(+),K(+)-ATPase, Ca(2+)-ATPase, and δ-aminolevulinate dehydratase (δ-ALA-D) in the brain, skeletal muscle, and blood were also assayed. Statistical analysis showed that the exhaustive exercise bout increased TBARS levels and DCFH-DA oxidation, and decreased NP-SH levels in rat tissue. Ca(2+)-ATPase activity was increased in groups exposed to both exercise and PGJ treatment. The results indicate that organic PGJ intake was able to protect against the oxidative damage caused by an exhaustive exercise bout in different rat tissues.

The influence of Bauhinia forficata Link subsp. pruinosa tea on lipid peroxidation and non-protein SH groups in human erythrocytes exposed to high glucose concentrations.

ETHNOPHARMACOLOGICAL RELEVANCE: Bauhinia forficata (BF) has been traditionally used as tea in folk medicine of Brazil for treatment of Diabetes mellitus (DM). AIM OF THE STUDY: To evaluate the effects of BF leaf tea on markers of oxidative damage and antioxidant levels in an experimental model of hyperglycemia in human erythrocytes in vitro. MATERIALS AND METHODS: Human erythrocytes were incubated with high glucose concentrations or glucose and BF tea for 24h and 48h. After incubation lipid peroxidation and non-protein SH levels were analyzed. Moreover, quantification of polyphenols and flavonoids, iron chelating property, scavenging of DPPH, and prevention of lipid peroxidation in isolated lipids were also assessed. RESULTS: A significant amount of polyphenols and flavonoids was observed. The main components found by LC-MS analysis were quercetin-3-O-(2-rhamnosyl) rutinoside, kaempferol-3-O-(2-rhamnosyl) rutinoside, quercetin-3-O-rutinoside and kaempferol-3-O-rutinoside. BF tea presents important antioxidant and chelating properties. Moreover, BF tea was effective to increase non-protein SH levels and reduce lipid peroxidation induced by high glucose concentrations in human erythrocytes. CONCLUSION: The antioxidant effects of BF tea could be related to the presence of different phenolic and flavonoids components. We believe that these components can be responsible to protect human erythrocytes exposed to high glucose concentrations against oxidative damage.

Swimming training induces liver mitochondrial adaptations to oxidative stress in rats submitted to repeated exhaustive swimming bouts.

BACKGROUND AND AIMS: Although acute exhaustive exercise is known to increase liver reactive oxygen species (ROS) production and aerobic training has shown to improve the antioxidant status in the liver, little is known about mitochondria adaptations to aerobic training. The main objective of this study was to investigate the effects of the aerobic training on oxidative stress markers and antioxidant defense in liver mitochondria both after training and in response to three repeated exhaustive swimming bouts. METHODS: Wistar rats were divided into training (n = 14) and control (n = 14) groups. Training group performed a 6-week swimming training protocol. Subsets of training (n = 7) and control (n = 7) rats performed 3 repeated exhaustive swimming bouts with 72 h rest in between. Oxidative stress biomarkers, antioxidant activity, and mitochondria functionality were assessed. RESULTS: Trained group showed increased reduced glutathione (GSH) content and reduced/oxidized (GSH/GSSG) ratio, higher superoxide dismutase (MnSOD) activity, and decreased lipid peroxidation in liver mitochondria. Aerobic training protected against exhaustive swimming ROS production herein characterized by decreased oxidative stress markers, higher antioxidant defenses, and increases in methyl-tetrazolium reduction and membrane potential. Trained group also presented higher time to exhaustion compared to control group. CONCLUSIONS: Swimming training induced positive adaptations in liver mitochondria of rats. Increased antioxidant defense after training coped well with exercise-produced ROS and liver mitochondria were less affected by exhaustive exercise. Therefore, liver mitochondria also adapt to exercise-induced ROS and may play an important role in exercise performance.

Therapeutic cold: An effective kind to modulate the oxidative damage resulting of a skeletal muscle contusion.

Muscular contusions affect the function of the skeletal muscle system. This study investigated the oxidative damage as well as the main morphological changes related to a skeletal muscle contusion in the gastrocnemius muscle of rats and also the capacity of therapeutic cold to modulate these parameters. The therapeutic cold modulated the increase of oxidative stress markers and also modulated the reduction in the antioxidants levels in the injured muscle. In enzyme assays, therapeutic cold was also effective in normalizing the muscle Na(+)/K(+) and Ca(2+) ATPases, lactate dehydrogenase and myeloperoxidase activities. Similarly, the lesioned non-treated animals presented evident impairments in the mitochondrial functions and in the muscle morphology which were diminished by the cold treatment. The therapeutic cold was able to modulate the oxidative damage possibly by its capacity to limit the inflammatory response intensity, to attenuate the impairment of the mitochondrial function and also to preserve the skeletal muscle morphology.

Anticonvulsant effect of GMP depends on its conversion to guanosine.

Studies on the purinergic system normally deal with adenine-based purines, namely, adenine nucleotides and adenosine. However, a guanine-based purinergic system may also have important neuromodulatory roles. Guanine-based purines exert trophic effects on neural cells, protect brain slices in a model of hypoxia and stimulate glutamate uptake. In vivo, both guanosine 5'-monophosphate (GMP) and guanosine (GUO) protected against seizures. In this study, we investigated if the anticonvulsant effect of GMP is mediated by guanosine and if guanosine or GMP treatments were able to increase adenosine levels. Intraperitoneal (i.p.) treatments with 7.5 mg/kg GMP or guanosine prevented 50% of seizures by quinolinic acid (QA) and increased guanosine cerebrospinal fluid (CSF) levels around twofold and threefold, respectively; GMP and adenosine levels remained unchanged. Intracerebroventricular treatment with 960 nmol GMP prevented 80% of seizures and the 5'-nucleotidase inhibitor alpha-beta-methyleneadenosine 5'-diphosphate (AOPCP), when injected 3 min before, reduced this anticonvulsant effect to 30% protection as well as significantly decreased the conversion of GMP into guanosine measured in the CSF. This study shows that the previously reported effect of GMP as an anticonvulsant seems to be related to its ability to generate guanosine through the action of ecto-5'-nucleotidase.