Effects of exercise on depressive behavior and striatal levels of norepinephrine, serotonin and their metabolites in sleep-deprived mice.

Exercise is a promising adjunctive therapy for depressive behavior, sleep/wake abnormalities, cognition and motor dysfunction. Conversely, sleep deprivation impairs mood, cognition and functional performance. The objective of this study is to evaluate the effects of exercise on anxiety and depressive behavior and striatal levels of norepinephrine (NE), serotonin and its metabolites in mice submitted to 6h of total sleep deprivation (6h-TSD) and 72h of Rapid Eye Movement (REM) sleep deprivation (72h-REMSD). Experimental groups were: (1) mice submitted to 6h-TSD by gentle handling; (2) mice submitted to 72h-REMSD by the flower pot method; (3) exercise (treadmill for 8 weeks); (4) exercise followed by 6h-TSD; (5) exercise followed by 72h-REMSD; (6) control (home cage). Behavioral tests included the Elevated Plus Maze and tail-suspension. NE, serotonin and its metabolites were determined in the striatum using high-performance liquid chromatography (HPLC). Sleep deprivation increased depressive behavior (time of immobilization in the tail-suspension test) and previous exercise hindered it. Sleep deprivation increased striatal NE and previous exercise reduced it. Exercise only was associated with higher levels of serotonin. Furthermore, exercise reduced serotonin turnover associated with sleep deprivation. In brief, previous exercise prevented depressive behavior and reduced striatal high NE levels and serotonin turnover. The present findings confirm the effects of exercise on behavior and neurochemical alterations associated with sleep deprivation. These findings provide new avenues for understanding the mechanisms of exercise.

HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum.

Efavirenz (EFV) is an effective antiretroviral drug with a favorable pharmacokinetic profile and widely used in combination regimens to treat HIV infection. However, there are major concerns about the safety of this drug. Patients treated with EFV often experience neuropsychiatric adverse effects, which frequently lead to switching to alternative EFV-free regimens. The mechanisms involved in the central action of EFV are intrinsically unclear. Thus, this study aimed to investigate the effects of acute and subchronic (2 weeks) EFV administration in a series of behavioral tests for anxiety-like and depression-like behavior in healthy rats. We also evaluated the effect of EFV treatment in striatal concentrations of monoamine neurotransmitters (serotonin, dopamine and noradrenaline) and their metabolites and the amino acid neurotransmitters glutamate and GABA. Our results showed that acute treatment with EFV induced an anxiogenic-like effect, while sub-chronic treatment induced both anxiogenic-like and depressive-like behavior which was dose related.. Additionally, EFV treatment caused marked alterations in the striatal concentrations of monoamines and their metabolites (and turnover rates) and the amino acid neurotransmitters glutamate and GABA. These changes were influenced by treatment duration and dose. These findings add more evidence about the neuropsychiatric adverse effects of EFV and propose potential new mechanisms for the toxic action of this drug in the central nervous system.

Differential effects of paradoxical sleep deprivation on memory and oxidative stress.

Sleep has important functions for every organ in the body and sleep deprivation (SD) leads to disorders that cause irreparable damage. The aim of this study was to investigate behavioral and brain structural alterations in mice deprived of paradoxical sleep for 48 and 72 h. Working memory, aversive memory as well as levels of nitric oxide (NO) and thiobarbituric acid reactive substances (TBARS) in the hippocampus, body striatum, and prefrontal cortex were evaluated. Working memory was affected in the 48- and 72-h SD groups while aversive memory was altered only in the 48-h SD group (p ≤ 0.05). Our findings showed that SD reduces NO levels in most brain areas (p < 0.05): NO levels were unaltered in the striatum of animals sleep-deprived for 48 h. Higher levels of TBARS were observed in all areas of the SD groups (p ≤ 0.05). Thus, we confirmed that SD has duration-dependent effects on behavior as well as on NO and TBARS levels in the brain. Preserved striatum NO levels suggest that this structure is less vulnerable to oxidative stress and is only affected by SD of longer duration. Increased TBARS and reduced NO levels in the hippocampus and prefrontal cortex confirm a central role for both these structures in working memory and aversive memory. Contextual fear conditioning was not affected by longer periods of SD. Thus, our findings suggest that shorter SD time may be more beneficial to avoid aversive memory where this may have implications for the management of posttraumatic stress.

Synergistic effect of the L-tryptophan and kynurenic acid with dipyrone or paracetamol in mice.

PURPOSE: Our great interest in this work was study the synergism between l-tryptophan and dipyrone or paracetamol as well as the interaction of kynurenic acid (l-tryptophan metabolite) and these analgesics agents utilizing a robust methodology. METHODS: We performed the writhing test induced by acetic acid in mice to evaluate the antinociceptive effect of the treatments isolated and combined (p.o. and i.p.). Dose-response curves were constructed and the values of ED50 for treatment alone and combined were statistically compared. In addition, isobolographic analysis was performed and the experimental values were compared with the theoretical values for simple additive effect. RESULTS: The combined treatment with l-tryptophan and dipyrone or paracetamol reduced significantly the ED50 of these analgesics when compared to the isolated treatments. l-tryptophan alone has no antinociceptive effect. l-Tryptophan increases the central amount of 5-HT and the synergism with dipyrone is antagonized by the 5-HT depletion. The kyna has an antinociceptive dose-related effect and a synergistic interaction with dipyrone and paracetamol verified by isobolographic analyses and confirmed by experimental values of ED50 of combined treatments were statistically lower than theoretical calculated values for simple additive effect. Melatonin antagonist receptor attenuates the antinociceptive synergism between l-tryptophan and dipyrone. CONCLUSION: Our results demonstrate that the increased 5-HT amount on the central nervous system is not per se capable to induce antinociception. The l-tryptophan interacts synergistically with dipyrone and paracetamol both orally and by i.p. route. This effect is dependent on the biotransformation of l-tryptophan to 5-HT and involves kynurenic acid and melatonin receptors.

Evaluation of the anti-inflammatory activity of riparin II (O-methil-N-2-hidroxi-benzoyl tyramine) in animal models.

Riparin II (RipII), an alkamide isolated from the green fruit of Aniba riparia, was tested in the various animal models of inflammation to investigate its anti-inflammatory activity. Male Wistar rats (180-240g) were treated with RipII by gavage at doses 25 or 50mg/kg, before initiating the inflammatory responses. The tests used were paw edema induced by carrageenan, dextran, histamine or serotonin; peritonitis induced by carrageenan and fMLP, as well as the measurement of MPO activity, TNF-α and Il-1ß amount in the peritoneal fluid. In the animal models of carrageenan and dextran-induced paw edema, the animals treated with RipII showed lower edema than those of the control group. Treatment with RipII also reduced the paw edema induced by histamine but not serotonin. In the carrageenan-induced peritonitis model, treatment with RipII reduced leukocyte migration, the MPO activity and the amount of TNF-α and IL-1ß in the peritoneal fluid. In summary, these results indicate that RipII has an anti-inflammatory activity in chemical models of acute inflammation. RipII might be directly or indirectly inhibiting the activity, production or release of pro-inflammatory mediators involved in the generation of the pain associated with inflammation.

The effects of the Brazilian ant Dinoponera quadriceps venom on chemically induced seizure models.

Arthropod venoms are potential sources of neuroactive substances, providing new tools for the design of drugs. The aim of this study was to evaluate the effects of Dinoponera quadriceps venom (DqV) on seizure models in mice induced by pentylenetetrazole (PTZ), pilocarpine, and strychnine. In the PTZ model, intraperitoneal treatment with DqV (0.5mg/kg) increased the time until the first seizure and the percentage of survival (155.4±27.7s/12.5%, p<0.05) compared to the control group (79.75±3.97s/0%), whereas endovenous treatment (0.1 and 0.5mg/kg) decreased the time until the first seizure (0.1mg/kg: 77.83±5.3s versus 101.0±3.3s in the control group; 0.5mg/kg: 74.43±3.9s versus 101.0±3.3s for the control group, p<0.05). We did not observe significant changes in the pilocarpine- and strychnine-induced seizure models. In assays that measured oxidative parameters in the PTZ model, intraperitoneal treatment with DqV (0.5 and 2.0mg/kg) only decreased the levels of MDA and nitrite in the cortex. However, endovenous treatment with DqV (0.1 and 0.5mg/kg) increased the levels of MDA in the cortex and hippocampus and at a dose of 0.5mg/kg in the striatum. Moreover, increased in nitrite content was observed in all three of the brain regions analyzed. Taken together, the D. quadriceps venom caused both neuroprotective and neurotoxic effects in a PTZ-induced seizure model, and this effect was dependent on the route of administration used.

TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate.

BACKGROUND: Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. METHODS: The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. RESULTS: CAT was administered intragastrically (25, 50, 75, 100 and 200 mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200 mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2 µg/paw), cinnamaldehyde (10 mmol/paw), menthol (1.2 mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. CONCLUSION: The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism.

Antinociceptive activity of carvacrol (5-isopropyl-2-methylphenol) in mice.

OBJECTIVES: Carvacrol (5-isopropyl-2-methylphenol) is a monoterpenic phenol which is present in the essential oil of oregano and thyme. We have investigated the behavioural effects of carvacrol in animal models of pain, such as acetic acid-induced abdominal constriction, formalin and hot-plate tests in mice. The spontaneous motor activity of animals treated with carvacrol was investigated using open-field and rotarod tests. METHODS: Carvacrol was administered orally, at single doses of 50 and 100 mg/kg while indometacin (5 mg/kg), morphine (7.5 mg/kg) and diazepam (2 mg/kg) were used as standard drugs. Naloxone (1 mg/kg) and l-arginine (150 mg/kg) were used to elucidate the possible antinociceptive mechanism of carvacrol on acetic acid-induced abdominal constriction and formalin tests. KEY FINDINGS: The results showed that carvacrol produced significant inhibitions on nociception in the acetic acid-induced abdominal constriction, formalin and hot-plate tests. In the open-field and rotarod tests carvacrol did not significantly impair the motor performance. The effect of the highest dose of carvacrol in mice in the acetic acid-induced abdominal constriction and formalin tests were not reversed by naloxone or l-arginine. CONCLUSIONS: Based on these results, it has been suggested that carvacrol presents antinociceptive activity that may not act through the opioid system nor through inhibition of the nitric oxide pathway.

(-)-α-Bisabolol-induced gastroprotection is associated with reduction in lipid peroxidation, superoxide dismutase activity and neutrophil migration.

This work examined the gastroprotection of (-)-α-bisabolol, an unsaturated optically active sesquiterpene alcohol obtained by the direct distillation essential oil from plants. (-)-α-Bisabolol has been described as a compound capable of reducing the gastric ulcer area in response to absolute ethanol. We evaluated the gastroprotection of (-)-α-bisabolol in ethanol-induced gastric lesions model through histopathological assessment, measurement of the membrane lipids peroxidation (MDA), myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, catalase (CAT) activity and the nitrite amount. Our results showed that (-)-α-bisabolol was able to reduce injuries associated with the administration of ethanol and the formation of thiobarbituric acid reactive substances (MDA) was also able to increase SOD activity and reduce the influx of cells inflammatory (neutrophils) in the gastric mucosa. The effect of (-)-α-bisabolol seems to be unrelated to the nitric oxide. (-)-α-Bisabolol caused a reduction of catalase activity. These findings show that (-)-α-bisabolol is able to decrease oxidative stress and inflammatory event associated with the lesions induced by ethanol.

Anti-nociceptive and anti-inflammatory activities of (-)-α-bisabolol in rodents.

(-)-α-Bisabolol is an unsaturated, optically active sesquiterpene alcohol obtained by the direct distillation of essential oil from plants such as Vanillosmopsis erythropappa and Matricaria chamomilla. (-)-α-Bisabolol has generated considerable economic interest, as it possesses a delicate floral odour and has been shown to have antiseptic and gastroprotective activities. In this study, (-)-α-bisabolol was tested in standardised rodent models by gavage administration at doses of 100 and 200 mg/kg in the models of inflammation and 25 and 50 mg/kg in the models of nociception. In the inflammatory models of paw oedema induced by carrageenan and dextran, the mice treated with (-)-α-bisabolol showed smaller oedemas compared to animals treated only with the vehicle. (-)-α-Bisabolol was capable of reducing paw oedemas induced by 5-HT but not oedemas induced by histamine. (-)-α-Bisabolol demonstrated anti-nociceptive activity in the models of visceral nociception induced by acetic acid and in the second phase of the nociception test induced by the intraplantar administration of formalin. (-)-α-Bisabolol did not have any effect in a thermal nociception model using a hot plate but was able to diminish mechanical inflammatory hypernociception evoked by carrageenan. These findings suggest that the anti-nociceptive action of (-)-α-bisabolol is not linked to a central mechanism but instead is related to the inflammatory process. (-)-α-Bisabolol was able to decrease leukocyte migration, protein extravasations and the amount of TNF-α to the peritoneal cavity in response to carrageenan. Additionally, (-)-α-bisabolol reduced neutrophil degranulation in response to phorbol-myristate-acetate. We demonstrate, for the first time, the peripheral anti-inflammatory and anti-nociceptive activities of (-)-α-bisabolol.

Mechanisms involved in the gastroprotective activity of esculin on acute gastric lesions in mice.

This work describes the gastroprotective actions of esculin (6,7-dihydroxycoumarin-6-o-glucoside) against indomethacin- or ethanol-induced lesions and verifies the role of nitric oxide, ATP-dependent K(+) channels, prostaglandins, transient receptor potential vanilloid 1 and antioxidant effects in the gastroprotective mechanism of esculin in the ethanol-induced gastric lesion model. The intragastric administration of esculin at doses of 12.5, 25 and 50 mg/kg was able to protect the gastric mucosa against ethanol (0.2 mL/animal p.o.), and esculin at doses of 25 and 50 mg/kg protected against indomethacin-induced lesions (20mg/kg p.o.). Administration of l-NAME (10mg/kg i.p.), glibenclamide (10mg/kg i.p.) or indomethacin (10mg/kg p.o.), but not capsazepine (5mg/kg p.o.), was able to reduce the gastroprotection promoted by esculin (25mg/kg) on the ethanol-induced lesions. Measurements of nitrite, a NO metabolite, were increased in the group that was pretreated with esculin. In terms of antioxidant activity as a gastroprotective mechanism of esculin, the results show that pre-treatment with esculin decreased the amount of GSH, increased SOD activity, did not interfere with the CAT activity and decreased both the MPO activity and the MDA amount. In conclusion, pre-treatment with esculin confers significant gastroprotective and antioxidant activity and leads to a reduction in gastric injury; the mechanisms underlying these effects include stimulation of endogenous prostaglandins, nitric oxide synthesis, opening of K(ATP) channels and reduction of free radicals or modulation of antioxidant enzyme systems.

Melatonin: pharmacological aspects and clinical trends.

Melatonin, N-acetyl-5-methoxytryptamine, the major hormone produced by the pineal gland under the influence of the dark/light cycle, has been shown to have a large number of therapeutic possibilities. It has been utilized in several countries for circadian rhythm disorders, sleep disturbances, jet lag, and sleep-wake cycle disturbances in blind people, and shift workers. In our mechanism of act, the G(i) protein-coupled metabotropic melatonin receptors MT1 and MT2 are the primary mediators of the physiological actions of melatonin. This hormone plays an important role in the regulation of physiological and neuroendocrine functions, such as synchronization of seasonal reproductive rhythms and entrainment of circadian cycles. In addition to its chronobiological role, several pharmacological effects of melatonin have been reported in mammals including sedative, antioxidant, anxiolytic, antidepressant, anticonvulsant, and analgesic activities. There is some evidence from clinical trials that melatonin can be helpful in that event. Current trends of pharmacological functions of melatonin pointed out its use in the treatment of neurodegenerative and neoplastic diseases. These effects and uses of melatonin are mentioned but further confirmatory studies are needed in most of them.

Anxiolytic-like effect of the monoterpene 1,4-cineole in mice.

Recent studies have shown that some monoterpenes exert anxiolytic- and depressant-like actions, however, these effects from monoterpene 1,4-cineole are still unknown. This work aimed to study the effects of 1,4-cineole in classic animal models for depression- and anxiety-like behavior, specifically the elevated plus maze (EPM), hole board, open field, pentobarbital sleeping time, forced swimming, tail suspension and rota rod tests. 1,4-Cineole was administered orally to mice (100, 200 and 400 mg/kg), while diazepam (1 or 2 mg/kg) and imipramine (10 or 30 mg/kg) were used as standard drugs. 1,4-Cineole (400 mg/kg) modified all parameters observed in the EPM, while no significant variation was observed on general motor activity in the open-field test. In the hole-board assay, 1,4-cineole induced increase on the number of head dips. Forced swimming and tail suspension tests showed that cineole (200 and/or 400 mg/kg) was able to promote significant increase on the immobility time, while a decreased sleep latency was observed (200 and 400 mg/kg ) on the pentobarbital sleeping time. Cineole had no effect on the motor coordination of animals in the rota rod test. The results suggest that 1,4-cineole presents potential anxiolytic-like action consistent with possible general depression of the CNS.

Vigilância pós-comercialização da Aguardente Alemã® (Operculina macrocarpa e Convolvulus scammonea) / Post-marketing surveillance of the Aguardente Alemã® (Operculina macrocarpa and Convolvulus scammonea)

A Aguardente Alemã (AA), produzida a partir dos extratos das raízes de Operculina macrocarpa e Convolvulus scammonia, conhecida, também, como “jalapa composta”, é indicadacomo laxante, mas é utilizada, popularmente, para as mais variadas patologias. Este trabalho objetivou delinear o perfi l do usuário desse fi toterápico, a forma de administração e as principais indicações de uso relatadas pelo usuário, utilizando, para isto, um questionário aplicado à população (n = 125) no momento da dispensação do produto em farmácias de Fortaleza, Ceará. Os usuários eram, na sua maioria, mulheres, com idade de 41 a 60 anos. A administração de AA era feita, em geral, com uma colher de chá (5 mL; 46,4%), uma vez por dia (87%), sem um horário fi xo de tomada; administrando com chá ou água, prioritariamente. A população referiuusar AA, principalmente, para problemas circulatórios (63%) e cefaléia (13,1%). A atividade purgativa, rotulada na formulação do produto comercializado, foi pouco referida. Desta feita, nossos resultados subsidiam importantes informações para o processo de certifi cação de AA junto às agências regulatórias e enfatizam a necessidade de mais estudos de vigilância póscomercialização, para a garantia do uso racional do produto pelo usuário.

The “Aguardente Alem㔠(AA), produced from extracts of the roots of Operculina macrocarpa and Convolvulus scammonea, also known as “composed jalapa”, is indicated as laxative, but it is used, popularly, for several diseases. Our objective was to delineate the user profi le of this herbal medicine, the way it is managed and the main use indications referred by users through a questionnaire applied to the population(n = 125) at the moment of the AA dispensing in community pharmacies of Fortaleza, Ceará. The users were mainly women, aged between 41 and 60 years. The administration of AA was generally done with a tea spoon (5 mL; 46.4%), once per day (87%), without an established time for taking; managing it with tea and water, principally. It was indicated by the population for using in diseases as circulatory problems (63%) and migraine (13.1%). The laxative activity, labeled in the formulation of the product, was poorly related. Thus, our results provide important information for the certifi cation process of AA to the regulatory agencies and emphasize thenecessity of more studies of post-marketing surveillance for the guarantee of the rational use of this product to the user.