Actions developed by the Brazilian Physiological Society to promote women's participation in science.

Here we described two activities related to Women in Science: one main conference and one symposium, both developed during the Annual Congress of the Brazilian Physiological Society, which were held within the XXXIII Annual Meeting of the Federation of Brazilian Experimental Biology Societies, from September 3-6, 2018, in Campos do Jordão (SP/Brazil). This conference and the symposium were among the most popular activities of the congress. This is important because the activities addressed important issues, including the fact that only 29% of the worlds' researchers are women, and women have difficulty progressing in a scientific career. Our report discusses why and which strategies could change this reality. We believe this symposium has not only contributed to advance and bring insights to physiological sciences, but, more importantly, it inspired and motivated physiologists to think about gender balance and the contribution and participation of women in physiological science.

Green Tea and Red Tea from Camellia sinensis Partially Prevented the Motor Deficits and Striatal Oxidative Damage Induced by Hemorrhagic Stroke in Rats.

Green tea from Camellia sinensis plays a well-established neuroprotective role in several neurodegenerative diseases, including intracerebral hemorrhage (ICH). However, the other teas of the same plant do not have their properties well understood; but they can be as effective as green tea as an alternative therapy. In this study, we investigated the effects of supplementation with green tea and red tea from Camellia sinensis on motor deficits and striatum oxidative damage in rats submitted to hemorrhagic stroke (ICH). Male Wistar rats were supplemented with green tea, red tea, or vehicle for 10 days prior to ICH induction. After injury, the rats were submitted to motor tests (open field for locomotion, rotarod for balance, and neurological deficit scale (NDS)) 1, 3, and 7 days after ICH induction, while the tea supplementation was maintained. Subsequently, the rats were euthanized to striatal tissue dissection for biochemical analyzes (lipid peroxidation, reactive oxygen species, glutathione levels, and total antioxidant capacity). ICH caused locomotor and balance deficits, as well as increased the neurological deficit (NDS). Only red tea prevented locomotor deficits after injury. Green tea and red tea prevented balance deficits on the seventh day after ICH. On NDS evaluation, green tea presented a better neuroprotection than red tea (until day 3 after ICH injury). In addition, ICH increased reactive oxygen species and lipid peroxidation levels, without altering antioxidant markers. Green and red teas were effective in decreasing the lipid peroxidation levels. Therefore, green and red teas partially prevented the motor deficits and striatal oxidative damage induced by ICH. Based on our results, we can consider that the two teas seem to be equally effective to prevent motor deficits and striatal oxidative damage induced by hemorrhagic stroke in rats.

Involvement of hippocampal CAMKII/CREB signaling in the spatial memory retention induced by creatine.

Although Creatine (Cr) and Phosphocreatine (PCr) systems play a key role in cellular energy and energy transport in neuronal cells, its implications for learning and memory are still controversial. Thus, we decided to investigate the involvement of cAMP-dependent protein kinase A (PKA), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and cAMP responsive element binding protein (CREB) in the spatial consolidation after an intrahippocampal injection of Cr. Statistical analysis revealed that Cr (2.5 nmol/hippocampus) (post-training) decreased the latency for escape and the mean number of errors on Barnes maze test. Post-training co-administration of the PKA inhibitor (H-89 25 ρmol/hippocampus) did not alter the facilitatory effect of Cr in this memory test. On the other hand, Cr-induced spatial retention was reverted by co-administration of the CaMKII inhibitor (STO-609 5 nmol/hippocampus). Neurochemical analysis revealed that intrahippocampal injection of Cr, when analyzed after 30 min rather than after 3 h, increased the levels of pCREB and pCaMKII but not pPKA levels. Statistical analysis also revealed that the post-training co-administration of STO-609 but not H-89 reversed the increase of pCREB levels induced by Cr. The results presented in this report suggest that intracellular CaMKII/CREB pathway plays a key role in the Cr-induced spatial retention. Thus, it is plausible to propose that Cr plays a putative role as a neuromodulator in the brain, and that at least some of its effects may be mediated by intracellular CaMKII/CREB pathway.

Swimming training prevents pentylenetetrazol-induced inhibition of Na+, K+-ATPase activity, seizures, and oxidative stress.

PURPOSE: In the present study we decided to investigate whether physical exercise protects against the electrographic, oxidative, and neurochemical alterations induced by subthreshold to severe convulsive doses of pentyltetrazole (PTZ). METHODS: The effect of swimming training (6 weeks) on convulsive behavior induced by PTZ (30, 45, and 60 mg/kg, i.p.) was measured and different electrographic electroencephalography (EEG) frequencies obtained from freely moving rats. After EEG recordings, reactive oxygen species (ROS) generation, nonprotein sulfhydryl (NPS), protein carbonyl, thiobarbituric acid-reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), Na(+), K(+)-ATPase activity, and glutamate uptake were measured in the cerebral cortex of rats. RESULTS: We showed that physical training increased latency and attenuated the duration of generalized seizures induced by administration of PTZ (45 mg/kg). EEG recordings showed that physical exercise decreased the spike amplitude after PTZ administration (all doses). Pearson's correlation analysis revealed that protection of physical training against PTZ-induced seizures strongly correlated with NPS content, Na(+), K(+)-ATPase activity, and glutamate-uptake maintenance. Physical training also increased SOD activity, NPS content, attenuated ROS generation per se, and was effective against inhibition of Na(+), K(+)-ATPase activity induced by a subthreshold convulsive dose of PTZ (30 mg/kg). In addition, physical training protected against 2',7'-dichlorofluorescein diacetate (DCFH-DA) oxidation, TBARS and protein carbonyl increase, decrease of NPS content, inhibition of SOD and catalase, and inhibition glutamate uptake induced by PTZ. CONCLUSIONS: These data suggest that effective protection of selected targets for free radical damage, such as Na(+), K(+)-ATPase, elicited by physical training protects against the increase of neuronal excitability and oxidative damage induced by PTZ.

Kinetic characterization of l-[(3)H]glutamate uptake inhibition and increase oxidative damage induced by glutaric acid in striatal synaptosomes of rats.

Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and striatal degeneration. Although growing evidence suggests that excitotoxicity and oxidative stress play central role in the neuropathogenesis of this disease, mechanism underlying striatal damage in this disorder is not well established. Thus, we decided to investigate the in vitro effects of GA 10nM (a low concentration that can be present initial development this disorder) on l-[(3)H]glutamate uptake and reactive oxygen species (ROS) generation in synaptosomes from striatum of rats. GA reduced l-[(3)H]glutamate uptake in synaptosomes from 1 up to 30min after its addition. Furthermore, we also provided some evidence that GA competes with the glutamate transporter inhibitor l-trans-pyrrolidine-2,4-dicarboxylate (PDC), suggesting a possible interaction of GA with glutamate transporters on synaptosomes. Moreover, GA produced a significant decrease in the V(MAX) of l-[(3)H]glutamate uptake, but did not affect the K(D) value. Although the GA did not show oxidant activity per se, it increased the ROS generation in striatal synaptosomes. To evaluate the involvement of reactive species generation in the GA-induced l-[(3)H]glutamate uptake inhibition, trolox (0.3, 0.6 and 6muM) was added on the incubation medium. Statistical analysis showed that trolox did not decrease inhibition of GA-induced l-[(3)H]glutamate uptake, but decreased GA-induced reactive species formation in striatal synaptosomes (1, 3, 5, 10, 15 and 30min), suggesting that ROS generation appears to occur secondarily to glutamatergic overstimulation in this model of organic acidemia. Since GA induced DCFH oxidation increase, we evaluate the involvement of glutamate receptor antagonists in oxidative stress, showing that CNQX, but not MK-801, decreased the DCFH oxidation increase in striatal synaptosomes. Furthermore, the results presented in this report suggest that excitotoxicity elicited by low concentration of GA, could be in part by maintaining this excitatory neurotransmitter in the synaptic cleft by non-competitive inhibition of glutamate uptake. Thus the present data may explain, at least partly, initial striatal damage at birth, as evidenced by acute bilateral destruction of caudate and putamen observed in children with GA-I.

Physical and cognitive training are able to prevent recognition memory deficits related to amyloid beta neurotoxicity.

Alzheimer's disease (AD) is characterized by the presence of amyloid-ß (Aß), oxidative damage and neuronal degeneration, which, together with other pathological events, promote progressive memory loss and cognitive decline. Non-pharmacological strategies have been study to provide some protection against the development of AD. Considering that physical exercise neuroprotective effects on prevention of cognitive deficits are well elucidate, it is important clarify the effects of cognitive training, and verify if they are similar or comparable to those observed for physical exercise. Here we divided male adult Wistar rats in six groups: control, which rats were not submitted to any intervention; Aß, which rats were submitted to hippocampal infusion of Aß; physical exercise (PE), which rats were submitted to 4 weeks of PE training; PE + Aß, which rats were submitted to 4 weeks of PE training followed by hippocampal infusion of Aß; cognitive exercise (CE), which rats were submitted to 4 weeks of CE training; and, CE + Aß, which rats were submitted to 4 weeks of CE training followed by hippocampal infusion of Aß. Ten days after Aß infusion, short (STM) and long-term (LTM) object recognition memory, as well as hippocampal oxidative stress (ROS levels by DCFH test), lipid peroxidation (TBARS), total antioxidant capacity (FRAP) and hippocampal histology were evaluated. Both PE and CE were effective in protect cognitive function against memory deficits related to Aß neurotoxicity, preventing oxidative stress and damage and hippocampal cellular disorganization. So, cognitive training seems to be as good as physical training in the prevention of memory deficits related to Aß and seems to share some mechanisms of actions, as oxidative stress prevention.

L-NAME prevents GM1 ganglioside-induced vasodilation in the rat brain.

Monosialoganglioside (GM1) is a glycosphingolipid present in most cell membranes that displays antioxidant and neuroprotective properties. It has been recently described that GM1 induces vasodilation. However, the mechanisms underlying GM1-induced vasodilation were not evaluated to date. Therefore, in this study we investigated whether the nonspecific NOS inhibitor l-NAME prevents GM1-induced vasodilation in rats. The systemic injection of GM1 (50mg/kg, i.p.) increased the outer diameter of pial vessels by 50% in anesthetized animals at 30min, and this effect was fully prevented by the administration of the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 60mg/kg, i.p. 15min before GM1 injection). A 30min exposure of cerebral cortex slices to GM1 (100microM) increased the content of nitrite plus nitrate (NOx) by 50%. Addition of l-NAME (100microM) to the incubation medium fully prevented GM1-induced NOx increase. Conversely, a 60min exposure of slices to GM1 (100microM) decreased NOx content, revealing a biphasic effect of GM1. Our results suggest that NO plays an important role in the vasodilation induced by GM1.

Na+,K+-ATPase activity impairment after experimental traumatic brain injury: relationship to spatial learning deficits and oxidative stress.

Traumatic brain injury (TBI) is a devastating disease that commonly causes persistent mental disturbances and cognitive deficits. Although studies indicate that oxidative stress and functional deficits occurring after TBI are interrelated events, the knowledge of the mechanisms underlying the development of such cognitive deficits has been limited. Thus, in the present study, we investigated the effect of fluid percussion brain injury (FPI) on a spatial learning task and levels of oxidative stress markers, namely, protein carbonylation and thiobarbituric acid-reactive substances (TBARS) and Na+,K+-ATPase activity 1 or 3 months after FPI in rats. Statistical analysis revealed that FPI increased the scape latency and mean number of error in Barnes maze test 1 and 3 months after FPI. We also found that protein carbonylation and TBARS content increased in the parietal cortex 1 and 3 months after FPI. In addition, 3 months after FPI, protein carbonylation levels increased both in ipsilateral and contralateral cortices of FPI animals. Indeed, statistical analysis revealed a decrease in Na+,K+-ATPase activity in the cerebral cortex of 1 month FPI animals. Furthermore, the decrease in enzyme activity found 3 months was larger, when compared with 1 month after FPI. These results suggest that cognitive impairment following TBI may result, at least in part, from increase of two oxidative stress markers, protein carbonylation and TBARS that occurs concomitantly to a decrease in Na+,K+-ATPase activity.

Short-term green tea supplementation prevents recognition memory deficits and ameliorates hippocampal oxidative stress induced by different stroke models in rats.

This study investigated the effect of green tea (GT) on short and long term declarative memory and oxidative damage induced by transient ischemia-reperfusion (IR) and intracerebral hemorrhage (ICH) in rats. Male Wistar rats were divided into 8 groups of 10 according the stroke type induced: Sham IR, Sham IR+GT, IR, IR+GT, Sham ICH, Sham ICH+GT, ICH, ICH+GT. Supplementation with GT was initiated 10days before stroke surgery and continuous for 6days after (GT dose 400mg/kg). Short (STM) and long term memory (LTM) we evaluated with object recognition task (OR) and hippocampus were used to evaluate parameters related to oxidative stress (ROS, lipid peroxidation and total antioxidant capacity). The rats subjected to IR and ICH showed STM and LTM deficits and GT intervention prevented it in both stroke models. IR and ICH induced increase on ROS levels in hippocampus. ICH increased the lipid peroxidation in hippocampus and the GT supplementation avoided it. IR induced decrease on total antioxidant capacity and GT prevented it. These results reveal that GT supplementation presents a neuroprotective role, attenuates redox imbalance and might have a beneficial impact on cognitive function after stroke.

Physical exercise prevents short and long-term deficits on aversive and recognition memory and attenuates brain oxidative damage induced by maternal deprivation.

It is known from previous research that physical exercise prevents long-term memory deficits induced by maternal deprivation in rats. But we could not assume similar effects of physical exercise on short-term memory, as short- and long-term memories are known to result from some different memory consolidation processes. Here we demonstrated that, in addition to long-term memory deficit, the short-term memory deficit resultant from maternal deprivation in object recognition and aversive memory tasks is also prevented by physical exercise. Additionally, one of the mechanisms by which the physical exercise influences the memory processes involves its effects attenuating the oxidative damage in the maternal deprived rats' hippocampus and prefrontal cortex.

Caffeine supplementation modulates oxidative stress markers in the liver of trained rats.

AIMS: Caffeine has been widely used in sports competitions due to its ergogenic effects. Most of the studies regarding caffeine and exercise have focused on muscle and plasma adaptations, while the impact on the liver is scarcely described. The aim is to analyze the effects of caffeine and exercise training on oxidative stress markers and injury-related parameters in the liver. MAIN METHODS: Rats were divided into sedentary/saline, sedentary/caffeine, exercise/saline, and exercise/caffeine groups. Exercise groups underwent 4 weeks of swimming training, and caffeine (6 mg/kg, p.o.) was supplemented throughout the training protocol. Injury-related liver parameters were assessed in plasma, while redox status and oxidative stress markers were measured on liver homogenates. KEY FINDINGS: Exercise training increased muscle citrate synthase activity in the muscle, while in caffeine decreased its activity in both sedentary and trained rats. Aspartate transaminase levels were increased after training, and caffeine intake suppressed this elevation (p<0.05). Caffeine also diminished alanine transaminase levels in both sedentary and exercised rats (p<0.05). Exercise training induced a significant increase on the activity of the enzymes superoxide dismutase and glutathione peroxidase, as an increase on thiobarbituric acid-reactive substances levels was also reached (p<0.05); caffeine intake blunted these alterations. Caffeine intake also suppressed liver catalase activity in both sedentary and exercise groups (p<0.05). SIGNIFICANCE: Our data suggest that caffeine modified the hepatic responses associated to exercise-induced oxidative stress without affecting the performance, exerting different actions according to the tissue. However, further studies are needed to better understand caffeine's role on liver under exercise training.

Caffeine intake may modulate inflammation markers in trained rats.

Caffeine is presented in many commercial products and has been proven to induce ergogenic effects in exercise, mainly related to redox status homeostasis, inflammation and oxidative stress-related adaptation mechanisms. However, most studies have mainly focused on muscle adaptations, and the role of caffeine in different tissues during exercise training has not been fully described. The aim of this study was therefore, to analyze the effects of chronic caffeine intake and exercise training on liver mitochondria functioning and plasma inflammation markers. Rats were divided into control, control/caffeine, exercise, and exercise/caffeine groups. Exercise groups underwent four weeks of swimming training and caffeine groups were supplemented with 6 mg/kg/day. Liver mitochondrial swelling and complex I activity, and plasma myeloperoxidase (MPO) and acetylcholinesterase (AChE) activities were measured. An anti-inflammatory effect of exercise was evidenced by reduced plasma MPO activity. Additionally, caffeine intake alone and combined with exercise decreased the plasma AChE and MPO activities. The per se anti-inflammatory effect of caffeine intake should be highlighted considering its widespread use as an ergogenic aid. Therefore, caffeine seems to interfere on exercise-induced adaptations and could also be used in different exercise-related health treatments.

Antioxidant activity elicited by low dose of caffeine attenuates pentylenetetrazol-induced seizures and oxidative damage in rats.

Although caffeine supplementation has a beneficial effect on people with neurological disorders, its implications for oxidative damage related to seizures are not well documented. Thus the aim of this study was to investigate the effects of two weeks caffeine supplementation (6mg/kg; p.o.) on seizures and neurochemical alterations induced by pentylenetetrazol (PTZ 60mg/kg i.p.). Statistical analyses showed that long-term rather than single dose caffeine administration decreased the duration of PTZ-induced seizures in adult male Wistar rats as recorded by cortical electroencephalographic (EEG) and behavioral analysis. The quantification of EEG recordings also revealed that caffeine supplementation protected against a wave increase induced by PTZ. Neurochemical analyses revealed that caffeine supplementation increased glutathione (GSH) content per se and protected against the increase in the levels of thiobarbituric acid reactive substances (TBARS) and oxidized diclorofluoresceine diacetate (DCFH-DA). Also, caffeine prevent the decrease in GSH content and Na(+), K(+)-ATPase activity induced by PTZ. Our data also showed that the infusion of L-buthionine sulfoximine (BSO; 3.2µmol/site i.c.v), an inhibitor of GSH synthesis, two days before injecting PTZ reversed the anticonvulsant effect caused by caffeine. BSO infusion also decreased GSH content and Na(+), K(+)-ATPase activity. However, it increased DCFH-DA oxidation and TBARS per se and reversed the protective effect of caffeine. Results presented in this paper support the neuroprotective effects of low long-term caffeine exposure to epileptic damage and suggest that the increase in the cerebral GSH content caused by caffeine supplementation may provide a new therapeutic approach to the control of seizure.

Exercise pre-conditioning reduces brain inflammation and protects against toxicity induced by traumatic brain injury: behavioral and neurochemical approach.

Although the favorable effects of physical exercise in neurorehabilitation after traumatic brain injury (TBI) are well known, detailed pathologic and functional alterations exerted by previous physical exercise on post-traumatic cerebral inflammation have been limited. In the present study, it is showed that fluid percussion brain injury (FPI) induced motor function impairment, followed by increased plasma fluorescein extravasation and cerebral inflammation characterized by interleukin-1ß, tumor necrosis factor-α (TNF-α) increase, and decreased IL-10. In addition, myeloperoxidase (MPO) increase and Na⁺,K⁺-ATPase activity inhibition after FPI suggest that the opening of blood-brain barrier (BBB) followed by neurtrophils infiltration and cerebral inflammation may contribute to the failure of selected targets leading to secondary damage. In fact, Pearson's correlation analysis revealed strong correlation of MPO activity increase with Na⁺,K⁺-ATPase activity inhibition in sedentary rats. Statistical analysis also revealed that previous running exercise (4 weeks) protected against FPI-induced motor function impairment and fluorescein extravasation. Previous physical training also induced IL-10 increase per se and protected against cerebral IL-1ß, and TNF-α increase and IL-10 decrease induced by FPI. This protocol of physical training was effective against MPO activity increase and Na⁺,K⁺-ATPase activity inhibition after FPI. The present protection correlated with MPO activity decrease suggests that the alteration of cerebral inflammatory status profile elicited by previous physical training reduces initial damage and limits long-term secondary degeneration after TBI. This prophylactic effect may facilitate functional recovery in patients suffering from brain injury induced by TBI.

Lipopolysaccharide enhances glutaric acid-induced seizure susceptibility in rat pups: behavioral and electroencephalographic approach.

Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and seizures. Considering that seizures are precipitated by common infections in children with GA-I, we investigated whether lipopolysaccharide (LPS) modifies GA-induced electrographic and neurochemical alterations in 21 days-old rats. The effect of LPS on convulsive behavior and electroencephalographic (EEG) alterations induced by GA (0.13; 0.4; 1.3 µmol/striatum) was determined in freely moving rats. After EEG recordings, we measured the levels of interleukin 1ß (IL-1ß) in GA-injected striatum. The injection of LPS (2mg/kg; i.p.) 6h before of GA administration, reduced the latency and increased the duration of seizures induced by GA (1.3 µmol/site). In addition, LPS administration increased IL-1ß striatal levels, which positively correlated with total time in seizures. The intrastriatal injection of an IL-1ß antibody (200 ng/2 µl) prevented the facilitation of GA-induced seizures by LPS. These data suggest that inflammatory processes during critical periods of development may decrease GA-induced seizure threshold.

Adaptation to oxidative challenge induced by chronic physical exercise prevents Na+,K+-ATPase activity inhibition after traumatic brain injury.

Physical exercise is likely to alter brain function and to afford neuroprotection in several neurological diseases. Although the favorable effects of physical exercise on traumatic brain injury (TBI) patients is well known, little information is available regarding the role of free radicals in the improvement induced by physical exercise in an experimental model of TBI induced by fluid percussion injury (FPI). Thus, we investigated whether 6 weeks of swimming training protects against oxidative damage (measured by protein carbonylation and thiobarbituric acid-reactive substances-TBARS) and neurochemical alterations represented by immunodetection of alpha subunit and activity of Na(+),K(+)-ATPase after FPI in cerebral cortex of rats. Statistical analysis revealed that physical training protected against FPI-induced TBARS and protein carbonylation increase. In addition, physical training was effective against Na(+),K(+)-ATPase enzyme activity inhibition and alpha(1) subunit level decrease after FPI. Pearson's correlation analysis revealed that the decrease in levels of catalytic alpha(1) subunit of Na(+),K(+)-ATPase induced FPI correlated with TBARS and protein carbonylation content increase. Furthermore, the effective protection exerted by physical training against FPI-induced free radical correlated with the immunocontent of the catalytic alpha(1) subunit maintenance. These data suggest that TBI-induced reactive oxygen species (ROS) generation decreases Na(+),K(+)-ATPase activity by decreasing the total number of enzyme molecules, and that physical exercise protects against this effect. Therefore, the effective protection of selected targets, such as Na(+),K(+)-ATPase induced by physical training, supports the idea that physical training may exert prophylactic effects on neuronal cell dysfunction and damage associated with TBI.

Methylmalonate-induced seizures are attenuated in inducible nitric oxide synthase knockout mice.

Methylmalonic acidemias consist of a group of inherited neurometabolic disorders caused by deficiency of methylmalonyl-CoA mutase activity clinically and biochemically characterized by neurological dysfunction, methylmalonic acid (MMA) accumulation, mitochondrial failure and increased reactive species production. Although previous studies have suggested that nitric oxide (NO) plays a role in the neurotoxicity of MMA, the involvement of NO-induced nitrosative damage from inducible nitric oxide synthase (iNOS) in MMA-induced seizures are poorly understood. In the present study, we showed a decrease of time spent convulsing induced by intracerebroventricular administration of MMA (2 micromol/2 microL; i.c.v.) in iNOS knockout (iNOS(-/-)) mice when compared with wild-type (iNOS(+/+)) littermates. Visual analysis of electroencephalographic recordings (EEG) showed that MMA injection induced the appearance of high-voltage synchronic spike activity in the ipsilateral cortex which spreads to the contralateral cortex while quantitative electroencephalographic analysis showed larger wave amplitude during MMA-induced seizures in wild-type mice when compared with iNOS knockout mice. We also report that administration of MMA increases NOx (NO(2) plus NO(3) content) and 3-nitrotyrosine (3-NT) levels in a greater extend in iNOS(+/+) mice than in iNOS(-/-) mice, indicating that NO overproduction and NO-mediated damage to proteins are attenuated in iNOS knockout mice. In addition, the MMA-induced decrease in Na(+), K(+)-ATPase activity, but not in succinate dehydrogenase (SDH) activity, was less pronounced in iNOS(-/-) when compared with iNOS(+/+) mice. These results reinforce the assumption that metabolic collapse contributes for the secondary toxicity elicited by MMA and suggest that oxidative attack by NO derived from iNOS on selected target such as Na(+), K(+)-ATPase enzyme might represent an important role in this excitotoxicity induced by MMA. Therefore, these results may be of value in understating the pathophysiology of the neurological features observed in patients with methylmalonic acidemia and in the development of new strategies for treatment of these patients.

Additive anticonvulsant effects of creatine supplementation and physical exercise against pentylenetetrazol-induced seizures.

Although physical activity and creatine supplementation have been a documented beneficial effect on neurological disorders, its implications for epilepsy are still controversial. Thus, we decided to investigate the effects of 6 weeks swimming training, creatine supplementation (300 mg/kg; p.o.) or its combination seizures and neurochemical alterations induced by pentylenetetrazol (PTZ). We found that 6 weeks of physical training or creatine supplementation decreased the duration of PTZ-induced seizures in adult male Wistar rats, as measured by cortical and hippocampal electroencephalography and behavioral analysis. Importantly, the combination between physical training and creatine supplementation had additive anticonvulsant effects, since it increased the onset latency for PTZ-induced seizures and was more effective in decrease seizure duration than physical training and creatine supplementation individually. Analysis of selected parameters of oxidative stress and antioxidant defenses in the hippocampus revealed that physical training, creatine supplementation or its combination abrogated the PTZ-elicited increase in levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonylation, as well as decrease in non-protein-thiols content, catalase (CAT) and SOD activities. In addition, this protocol of physical training and creatine supplementation prevented the PTZ-induced decrease in hippocampal Na+,K+-ATPase activity. Altogether, these results suggest that protection elicited physical training and creatine supplementation of selected targets for reactive species-mediated damage decrease of neuronal excitability and consequent oxidative damage elicited by PTZ. In conclusion, the present study shows that physical training, creatine supplementation or its combination attenuated PTZ-induced seizures and oxidative damage in vivo, and provide evidence that combination between creatine supplementation and physical exercise may be a useful strategy in the treatment of convulsive disorders.