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Brain serotonin and dopamine are neurotransmitters related to fatigue, a feeling that leads to reduced intensity or interruption of physical exercises, thereby regulating performance. The present review aims to present advances on the understanding of fatigue, which has recently been proposed as a defense mechanism instead of a "physiological failure" in the context of prolonged (aerobic) exercises. We also present recent advances on the association between serotonin, dopamine and fatigue. Experiments with rodents, which allow direct manipulation of brain serotonin and dopamine during exercise, clearly indicate that increased serotoninergic activity reduces performance, while increased dopaminergic activity is associated with increased performance. Nevertheless, experiments with humans, particularly those involving nutritional supplementation or pharmacological manipulations, have yielded conflicting results on the relationship between serotonin, dopamine and fatigue. The only clear and reproducible effect observed in humans is increased performance in hot environments after treatment with inhibitors of dopamine reuptake. Because the serotonergic and dopaminergic systems interact with each other, the serotonin-to-dopamine ratio seems to be more relevant for determining fatigue than analyzing or manipulating only one of the two transmitters. Finally, physical training protocols induce neuroplasticity, thus modulating the action of these neurotransmitters in order to improve physical performance.

Hypertension is characterized by a pro-inflammatory status, including redox imbalance and increased levels of pro-inflammatory cytokines, which may be exacerbated after heat exposure. However, the effects of heat exposure, specifically in individuals with inflammatory chronic diseases such as hypertension, are complex and not well understood. This study compared the effects of heat exposure on plasma cytokine levels and redox status parameters in 8 hypertensive (H) and 8 normotensive (N) subjects (age: 46.5±1.3 and 45.6±1.4 years old, body mass index: 25.8±0.8 and 25.6±0.6 kg/m2, mean arterial pressure: 98.0±2.8 and 86.0±2.3 mmHg, respectively). They remained at rest in a sitting position for 10 min in a thermoneutral environment (22°C) followed by 30 min in a heated environmental chamber (38°C and 60% relative humidity). Blood samples were collected before and after heat exposure. Plasma cytokine levels were measured using sandwich ELISA kits. Plasma redox status was determined by thiobarbituric acid reactive substances (TBARS) levels and ferric reducing ability of plasma (FRAP). Hypertensive subjects showed higher plasma levels of IL-10 at baseline (P<0.05), although levels of this cytokine were similar between groups after heat exposure. Moreover, after heat exposure, hypertensive individuals showed higher plasma levels of soluble TNF receptor (sTNFR1) and lower TBARS (P<0.01) and FRAP (P<0.05) levels. Controlled hypertensive subjects, who use angiotensin-converting-enzyme inhibitor (ACE inhibitors), present an anti-inflammatory status and balanced redox status. Nevertheless, exposure to a heat stress condition seems to cause an imbalance in the redox status and an unregulated inflammatory response.

Individuals with systemic arterial hypertension have a higher risk of heat-related complications. Thus, the aim of this study was to examine the thermoregulatory responses of hypertensive subjects during recovery from moderate-intensity exercise performed in the heat. A total of eight essential hypertensive (H) and eight normotensive (N) male subjects (age=46.5±1.3 and 45.6±1.4 years, body mass index=25.8±0.8 and 25.6±0.6 kg/m2, mean arterial pressure=98.0±2.8 and 86.0±2.3 mmHg, respectively) rested for 30 min, performed 1 h of treadmill exercise at 50% of maximal oxygen consumption, and rested for 1 h after exercise in an environmental chamber at 38°C and 60% relative humidity. Skin and core temperatures were measured to calculate heat exchange parameters. Mean arterial pressure was higher in the hypertensive than in the normotensive subjects throughout the experiment (P<0.05, unpaired t-test). The hypertensive subjects stored less heat (H=-24.23±3.99 W·m-2vs N=-13.63±2.24 W·m-2, P=0.03, unpaired t-test), experienced greater variations in body temperature (H=-0.62±0.05°C vsN=-0.35±0.12°C, P=0.03, unpaired t-test), and had more evaporated sweat (H=-106.1±4.59 W·m-2vs N=-91.15±3.24 W·m-2, P=0.01, unpaired t-test) than the normotensive subjects during the period of recovery from exercise. In conclusion, essential hypertensive subjects showed greater sweat evaporation and increased heat dissipation and body cooling relative to normotensive subjects during recovery from moderate-intensity exercise performed in hot conditions.

The aim of this study was to investigate the effect of adding whole-body vibration (WBV; frequency = 35 to 40 Hz; amplitude = 4 mm) to squat training on the T-cell proliferative response of elderly patients with osteoarthritis (OA) of the knee. This study was a randomized controlled trial in which the selected variables were assessed before and after 12 weeks of training. Twenty-six subjects (72 ± 5 years of age) were divided into three groups: 1) squat training with WBV (WBV, N = 8); 2) squat training without WBV (N = 10), and 3) a control group (N = 8). Women who were ≥60 years of age and had been diagnosed with OA in at least one knee were eligible. The intervention consisted of 12 uninterrupted weeks of squatting exercise training performed 3 times/week. Peripheral blood mononuclear cells were obtained from peripheral blood collected before and after training. The proliferation of TCD4+ and TCD8+ cells was evaluated by flow cytometry measuring the carboxyfluorescein succinimidyl ester fluorescence decay before and after the intervention (∆). The proliferative response of TCD4+ cells (P = 0.02, effect size = 1.0) showed a significant decrease (23%) in the WBV group compared to the control group, while there was no difference between groups regarding the proliferative response of TCD8+ cells (P = 0.12, effect size = 2.23). The data suggest that the addition of WBV to squat exercise training might modulate T-cell-mediated immunity, minimizing or slowing disease progression in elderly patients with OA of the knee.

Chronic neurodegenerative processes have been identified in the rat forebrain after prolonged survival following hyperthermia (HT) initiated a few hours after transient global ischemia. Since transient global ischemia and ischemic penumbra share pathophysiological similarities, this study addressed the effects of HT induced after recirculation of focal brain ischemia on infarct size during long survival times. Adult male Wistar rats underwent intra-luminal occlusion of the left middle cerebral artery for 60 min followed by HT (39.0-39.5 degrees C) or normothermia. Control procedures included none and sham surgery with and without HT, and middle cerebral artery occlusion alone. Part I: 6-h HT induced at recirculation. Part II: 2-h HT induced at 2-, 6-, or 24-h recirculation. Part III: 2-h HT initiated at recirculation or 6-h HT initiated at 2-, 6- or 24-h recirculation. Survival periods were 7 days, 2 or 6 months. The effects of post-ischemic HT on cortex and striatum were evaluated histopathologically by measuring the area of remaining tissue in the infarcted hemisphere at -0.30 mm from bregma. Six-hour HT initiated from 6-h recirculation caused a significant decrease in the remaining cortical tissue between 7-day (N = 8) and 2-month (N = 8) survivals (98.46 +/- 1.14 to 73.62 +/- 8.99%, respectively). When induced from 24-h recirculation, 6-h HT caused a significant reduction of the remaining cortical tissue between 2- (N = 8) and 6-month (N = 9) survivals (94.97 +/- 5.02 vs 63.26 +/- 11.97%, respectively). These data indicate that post-ischemic HT triggers chronic neurodegenerative processes in ischemic penumbra, suggesting that similar fever-triggered effects may annul the benefit of early recirculation in stroke patients over the long-term.

Abnormal riboflavin status in the absence of a dietary deficiency was detected in 31 consecutive outpatients with Parkinson's disease (PD), while the classical determinants of homocysteine levels (B6, folic acid, and B12) were usually within normal limits. In contrast, only 3 of 10 consecutive outpatients with dementia without previous stroke had abnormal riboflavin status. The data for 12 patients who did not complete 6 months of therapy or did not comply with the proposed treatment paradigm were excluded from analysis. Nineteen PD patients (8 males and 11 females, mean age +/- SD = 66.2+/-8.6 years; 3, 3, 2, 5, and 6 patients in Hoehn and Yahr stages I to V) received riboflavin orally (30 mg every 8 h) plus their usual symptomatic medications and all red meat was eliminated from their diet. After 1 month the riboflavin status of the patients was normalized from 106.4+/-34.9 to 179.2+/-23 ng/ml (N = 9). Motor capacity was measured by a modification of the scoring system of Hoehn and Yahr, which reports motor capacity as percent. All 19 patients who completed 6 months of treatment showed improved motor capacity during the first three months and most reached a plateau while 5/19 continued to improve in the 3- to 6-month interval. Their average motor capacity increased from 44 to 71% after 6 months, increasing significantly every month compared with their own pretreatment status (P < 0.001, Wilcoxon signed rank test). Discontinuation of riboflavin for several days did not impair motor capacity and yellowish urine was the only side effect observed. The data show that the proposed treatment improves the clinical condition of PD patients. Riboflavin-sensitive mechanisms involved in PD may include glutathione depletion, cumulative mitochondrial DNA mutations, disturbed mitochondrial protein complexes, and abnormal iron metabolism. More studies are required to identify the mechanisms involved.

The data reviewed here suggest the possibility that a global reduction of blood supply to the whole brain or solely to the infratentorial structures down to the range of ischemic penumbra for several hours or a few days may lead to misdiagnosis of irreversible brain or brain stem damage in a subset of deeply comatose patients with cephalic areflexia. The following proposals are advanced: 1) the lack of any set of clinically detectable brain functions does not provide a safe diagnosis of brain or brain stem death; 2) apnea testing may induce irreversible brain damage and should be abandoned; 3) moderate hypothermia, antipyresis, prevention of arterial hypotension, and occasionally intra-arterial thrombolysis may contribute to good recovery of a possibly large subset of cases of brain injury currently regarded as irreversible; 4) confirmatory tests for brain death should not replace or delay the administration of potentially effective therapeutic measures; 5) in order to validate confirmatory tests, further research is needed to relate their results to specific levels of blood supply to the brain. The current criteria for the diagnosis of brain death should be revised.

We have shown that the renin-angiotensin system (RAS) is involved in glucose homeostasis during acute hemorrhage. Since almost all of the physiological actions described for angiotensin II were mediated by AT1 receptors, the present experiments were designed to determine the participation of AT1 receptors in the hyperglycemic action of angiotensin II in freely moving rats. The animals were divided into two experimental groups: 1) animals submitted to intravenous administration of angiotensin II (0.96 nmol/100 g body weight) which caused a rapid increase in plasma glucose reaching the highest values at 5 min after the injection (33% of the initial values, P < 0.01), and 2) animals submitted to intravenous administration of DuP-753 (losartan), a non-peptide antagonist of angiotensin II with AT1-receptor type specificity (1.63 mumol/100 g body weight as a bolus, i.v., plus a 30-min infusion of 0.018 mumol 100 g body weight-1 min-1 before the injection of angiotensin II), which completely blocked the hyperglycemic response to angiotensin II (P < 0.01). This inhibitory effect on glycemia was already demonstrable 5 min (8.9 +/- 0.28 mM, angiotensin II, N = 9 vs 6.4 +/- 0.22 mM, losartan plus angiotensin II, N = 11) after angiotensin II injection and persisted throughout the 30-min experiment. Controls were treated with the same volume of saline solution (0.15 M NaCl). These data demonstrate that the angiotensin II receptors involved in the direct and indirect hyperglycemic actions of angiotensin II are mainly of the AT1-type.

The effects of hyperprolactinemia on plasma prolactin (PRL) and glucose were investigated in female rats submitted to surgical stress (laparotomy under ether anesthesia). Wistar rats weighing 250-280 g received pituitary grafts under the kidney capsule three weeks before the experiments (N = 15) while a control group underwent sham transplantation (N = 14). The sham-operated rats presented a three-fold increase of PRL levels as early as after 5 min of surgical stress (P < 0.01); the PRL levels reached a peak at about 15 min and returned to baseline at 40 min. The PRL levels of the grafted rats were increased 3.5-fold compared to the sham-operated controls before stress (20.2 +/- 5.6 ng/ml vs 5.8 +/- 0.9 ng/ml, respectively; P < 0.05), but did not change significantly during the experimental period. Plasma glucose was already significantly increased at 5 min in sham-operated control and grafted rats (P < 0.01) and reached maximal concentrations at about 15 min. The grafted rats presented higher glucose levels than sham-operated controls before stress (122.2 +/- 3.3 vs 100.5 +/- 4.2 mg/dl; P < 0.01) and at 40 min (182.6 +/- 13.6 vs 146.7 +/- 8.4 mg/dl; P < 0.05). The hyperprolactinemic rats showed impaired surgical stress-induced PRL release and higher glucose levels both at rest and during the first postoperative hour. These results indicate that chronic hyperprolactinemia inhibited PRL secretion and enhanced the hyperglycemic stress response in the female rat.

Metabolic adjustment was studied in male Wistar rats weighing 180-200 g with bilateral electrolytic lesions in the preoptic area which were acclimatized to a hot environment (34 degrees C, 30 rats) and to normal temperature (25 degrees C, 20 rats) for 60 days. Oxygen consumption at 34 degrees C and body weight were measured periodically. Preoptic-lesioned rats (PO rats) showed a reduction in metabolic rate (from 46.2 +/- 2 to 33 +/- 2 Cal/m2 per h, P less than 0.05) regardless of the temperatures to which they were adapted. Although the reduced metabolic rate of PO rats living at 25 degrees C or 34 degrees C could be an indicator of adaptation to heat, only the PO rats living at 25 degrees C showed a weight gain (101 +/- 13 g) similar to that observed for the sham-operated control (75 +/- 11 g). In fact, the PO rats living at 34 degrees C failed to increase their body weight during 60 days of exposure to heat. These data indicate that the preoptic area is essential to integrate the thermal input with the energy-linked metabolic process involved in adaptation to hot environments.

The cold-adaptation process was examined in preoptic-lesioned (PO, 18 rats) and adrenaldemedullated-preoptic-lesioned rats (ADPO, 16 rats). PO rats and ADPO female Wistar rats were cold acclimatized to 5 degrees C for 2 operated and then treated exactly like the lesioned rats. Lesions in the PO region caused a decrease in the ability to maintain normal body temperature in a cold environment (5 degrees C for 2 h). Their colonic temperature fell even by the end of the 2nd h of cold exposure (-1.1 degrees C for PO rats and -1.25 degrees C for ADPO rats, P less than 0.01). However, after 2 weeks of cold acclimation the PO rats, but not the ADPO rats were able to thermoregulate in the cold and showed a normal increase in interscapular brown adipose tissue weight (79%, P less than 0.01). These data suggest that the PO is not an essential link for cold adaptation when a mild cold-adaptation method is used. Furthermore, the data show that increased adrenal medullary activity is required for the cold adaptation process in PO rats.

Metabolic adjustment was studied in rats with bilateral electrolytic lesions in the preoptic area which were exposed to heat (34 degrees C) and to normal temperature (25 degrees C) for 60 days. The metabolic rate measured at neutral temperature (29 degrees C) in preoptic-lesioned rats living at 25 degrees or 34 degrees C was reduced to 80% the rate of sham-operated controls. The increase in metabolic rate induced by heat (30 min at 34 degrees or 37 degrees C) in preoptic-lesioned rats, living at 25 degrees C, was markedly reduced to 10% the rate of sham-operated controls living at 25 degrees C. In preoptic-lesioned rats, the increased metabolic rate induced by heat exposure (34 degrees or 37 degrees C) was impaired, regardless of the living ambient temperature (25 degrees or 34 degrees C) of the animal. These data demonstrate the participation of the preoptic area in heat-induced increased oxygen consumption and provide additional evidence for its role in the integration of thermal inputs with energy-linked metabolic processes.

Because the pineal gland appears to be involved in the regulation of body electrolytes, saline or water preference was investigated in pinealectomized, adrenalectomized, pinealectomized-adrenalectomized, and sham-operated (SO) control rats. The pinealectomized, adrenalectomized, and pinealectomized-adrenalectomized rats exhibited increased saline consumption during the two postoperative weeks when compared with the SO-control animals. Water intake was similar for pinealectomized and SO-control rats, but decreased for pinealectomized-adrenalectomized, and adrenalectomized rats. Although total fluid intake increased for pinealectomized, and pinealectomized-adrenalectomized rats, the proportion of saline ingested in preference to water by pinealectomized-adrenalectomized rats was twice that exhibited by pinealectomized rats. The results showed two different behaviors: increased saline intake without changes in water intake by pinealectomized rats, and increased saline intake with decreased water intake by adrenalectomized rats. However, the higher saline intake induced by pinealectomy was further increased by adrenalectomy, suggesting a direct role for the pineal gland in mediating specific salt appetite.

1. The effects of post-ischemic hypothermia were studied in the gerbil brain. After 5 min of bilateral common carotid occlusion (BCCO) under thiopental anesthesia and normothermia (rectal temperature of 37 +/- 0.5 degrees C) 20 animals were maintained either normothermic (group NT, N = 10) or hypothermic (rectal temperature of 29 +/- 0.5 degrees C, obtained within 5 min of carotid recirculation) for 5 h (group HT, N = 10). Sham-operated animals (N = 5) were kept normothermic for 5 h following the surgical procedure. 2. After a 7-day period of survival, damage to the dorsal hippocampus was determined histopathologically by cresyl-violet staining and graded on a scale of 0 to 3. The histopathological damage observed in the CA1 subfield of the hippocampus was found to be more intense in NT than in HT gerbils (P less than 0.001, Mann-Whitney U-test). 3. These results suggest that moderate and short-lasting hypothermia induced early in the recirculation period protects the brain against ischemic injury. The importance of these results is discussed in terms of pathophysiology, treatment and interpretation of experimental brain ischemia data.

The motoneurons of the oculomotor complex responsible for controlling accommodation and pupil size of the marmoset were identified by injecting horseradish peroxidase (HRP) into the ciliary ganglion. The anatomical organization of accommodation and pupil constrictor motoneurons was determined using electrical stimulation techniques. HRP-labelled cells were found through the whole length of the Edinger-Westphal nucleus (EW) and also just ventral to this nucleus in caudal sections. A projection from the antero-median nucleus to the ciliary ganglion could not be demonstrated. Electrical stimulation data showed that currents of less than 1 microampere applied inside the EW evoked accommodation responses. Pupil constriction responses, on the other hand, were evoked with weak currents at sites ventral to those in the EW generating accommodation at caudal and central levels. It was concluded that the EW was responsible for accommodation and areas containing HRP-labelled cells ventral to the caudal part of the EW were responsible for pupil constriction.

1. The Pulsinelli preparation has largely simplified and avoided the complications of other models of brain ischemia in the rat. We present here modifications which improve the Pulsinelli preparation, based on a new and atraumatic technique for arterial clamping. Effective cauterization of vertebral arteries was obtained using a modified pyrographic device. Histopathological results demonstrate that the modified method was capable of reproducing the features of transient forebrain ischemia reported in the literature. 2. Consistent postural changes were induced by the ischemic insult. The intensity and interhemispheric symmetry of brain damage correlated well with the occurrence and maintenance of postural alterations throughout the ischemic period as well as with the duration of the latter.