Isoflavones prevent oxidative stress and inhibit the activity of the enzyme monoamine oxidase in vitro.

Oxidative stress occurs due to an imbalance between antioxidant defenses and pro-oxidant agents in brain. This condition has been associated to the pathogenesis of several brain diseases; therefore, increasing the use of compounds that exert antioxidant activity. Thus, the objective of this study was to evaluate, in vitro, the effect of isoflavones in: (1) lipid peroxidation, catalase activity and thiol groups in the presence of pro-oxidants: sodium nitroprusside or Fe2+/EDTA complex in rat brain homogenates; (2) the activity of the enzyme monoamine oxidase (MAO). As a result, the isoflavones reduced lipid peroxidation in a manner dependent on the concentration and protected against the reduction of catalase activity as well as the induced thiol oxidation in brain tissue. In addition, isoflavones inhibited MAO activity (MAO-A and MAO-B). Taken together, our results showed that isoflavones avoided oxidative stress and decreased the MAO activity, suggesting a promissory use in the treatment of neurodegenerative diseases.

Resveratrol Protects Against Vacuous Chewing Movements Induced by Chronic Treatment with Fluphenazine.

Typical antipsychotics, which are commonly used to treat schizophrenia, cause motor disorders such as tardive dyskinesia (TD) in humans and orofacial dyskinesia (OD) in rodents. The disease mechanisms as well as treatment effectiveness are still unknown. In this study, we investigated the effect of resveratrol, a polyphenol with neuroprotective properties, on behavioral changes induced by chronic treatment with fluphenazine in rats and the possible relationship between monoamine oxidase (MAO) activity and vacuous chewing movements (VCMs). Rats were treated for 18 weeks with fluphenazine enantate [25 mg/kg, intramuscularly (i.m.), every 21 days] and/or resveratrol (20 mg/kg, offered daily in drinking water). Next, body weight gain, behavioral parameters (VCMs and open field tests-locomotor and rearing activity), and MAO activity were evaluated. Fluphenazine treatment reduced body weight gain, number of crossings and rearings, and the co-treatment with resveratrol did not affect these alterations. Fluphenazine increased the prevalence and intensity of VCMs and the co-treatment with resveratrol reduced the VCMs. Furthermore, a negative correlation was found between the number of VCMs and MAO-B activity in the striatum of rats. Our data suggest that resveratrol could be promissory to decrease OD. Moreover, MAO-B activity in the striatum seems to be related to VCMs intensity.

Harpagophytum Procumbens Ethyl Acetate Fraction Reduces Fluphenazine-Induced Vacuous Chewing Movements and Oxidative Stress in Rat Brain.

Long-term treatment with fluphenazine is associated with manifestation of extrapyramidal side effects, such as tardive dyskinesia. The molecular mechanisms related to the pathophysiology of TD remain unclear, and several hypotheses, including a role for oxidative stress, have been proposed. Harpagophytum procumbens is an herbal medicine used mainly due to anti-inflammatory effects, but it also exhibits antioxidant effects. We investigated the effect of ethyl acetate fraction of H. procumbens (EAF HP) in fluphenazine-induced orofacial dyskinesia by evaluating behavioral parameters at different times (vacuous chewing movements (VCM's) and locomotor and exploratory activity), biochemical serological analyses, and biochemical markers of oxidative stress of the liver, kidney, cortex, and striatum. Chronic administration of fluphenazine (25 mg/kg, intramuscular (i.m) significantly increased the VCMs at all analyzed times (2, 7, 14, and 21 days), and this was inhibited by EAF HP (especially at a dose of 30 mg/kg). Fluphenazine decreased locomotion and exploratory activity, and EAF HP did not improve this decrease. Fluphenazine induced oxidative damage, as identified by changes in catalase activity and ROS levels in the cortex and striatum, which was reduced by EAF HP, especially in the striatum. In the cortex, EAF HP was protective against fluphenazine-induced changes in catalase activity but not against the increase in ROS level. Furthermore, EAF HP was shown to be safe, since affected serum biochemical parameters or parameters of oxidative stress in the liver and kidney. These findings suggest that the H. procumbens is a promising therapeutic agent for the treatment of involuntary oral movements.

Centella asiatica and Its Fractions Reduces Lipid Peroxidation Induced by Quinolinic Acid and Sodium Nitroprusside in Rat Brain Regions.

Oxidative stress has been implicated in several pathologies including neurological disorders. Centella asiatica is a popular medicinal plant which has long been used to treat neurological disturbances in Ayurvedic medicine. In the present study, we quantified of compounds by high performance liquid chromatography (HPLC) and examined the phenolic content of infusion, ethyl acetate, n-butanolic and dichloromethane fractions. Furthermore, we analyzed the ability of the extracts from C. asiatica to scavenge the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) radical as well as total antioxidant activity through the reduction of molybdenum (VI) (Mo(6+)) to molybdenum (V) (Mo(5+)). Finally, we examined the antioxidant effect of extracts against oxidant agents, quinolinic acid (QA) and sodium nitroprusside (SNP), on homogenates of different brain regions (cerebral cortex, striatum and hippocampus). The HPLC analysis revealed that flavonoids, triterpene glycoside, tannins, phenolic acids were present in the extracts of C. asiatica and also the phenolic content assay demonstrated that ethyl acetate fraction is rich in these compounds. Besides, the ethyl acetate fraction presented the highest antioxidant effect by decreasing the lipid peroxidation in brain regions induced by QA. On the other hand, when the pro-oxidant agent was SNP, the potency of infusion, ethyl acetate and dichloromethane fractions was equivalent. Ethyl acetate fraction from C. asiatica also protected against thiol oxidation induced by SNP and QA. Thus, the therapeutic potential of C. asiatica in neurological diseases could be associated to its antioxidant activity.

Bauhinia forficata prevents vacuous chewing movements induced by haloperidol in rats and has antioxidant potential in vitro.

Classical antipsychotics can produce motor disturbances like tardive dyskinesia in humans and orofacial dyskinesia in rodents. These motor side effects have been associated with oxidative stress production in specific brain areas. Thus, some studies have proposed the use of natural compounds with antioxidant properties against involuntary movements induced by antipsychotics. Here, we examined the possible antioxidant activity of Bauhinia forficata (B. forficata), a plant used in folk medicine as a hypoglycemic, on brain lipid peroxidation induced by different pro-oxidants. B. forficata prevented the formation of lipid peroxidation induced by both pro-oxidants tested. However, it was effective against lipid peroxidation induced by sodium nitroprusside (IC50 = 12.08 µg/mL) and Fe(2+)/EDTA (IC50 = 41.19 µg/mL). Moreover, the effects of B. forficata were analyzed on an animal model of orofacial dyskinesia induced by long-term treatment with haloperidol, where rats received haloperidol each 28 days (38 mg/kg) and/or B. forficata decoction daily (2.5 g/L) for 16 weeks. Vacuous chewing movements (VCMs), locomotor and exploratory activities were evaluated. Haloperidol treatment induced VCMs, and co-treatment with B. forficata partially prevented this effect. Haloperidol reduced the locomotor and exploratory activities of animals in the open field test, which was not modified by B. forficata treatment. Our present data showed that B. forficata has antioxidant potential and partially protects against VCMs induced by haloperidol in rats. Taken together, our data suggest the protection by natural compounds against VCMs induced by haloperidol in rats.

Effect of Hypericum perforatum on different models of movement disorders in rats.

The effects of Hypericum perforatum, a plant with antidepressant action, were evaluated in models of abnormal movements in rats, brought about by administration of fluphenazine or reserpine. The number of vacuous chewing movements (VCMs) and locomotor activity (the number of crossings and rears in the open field test) were measured. In experiment 1, rats received a single administration of fluphenazine enanthate (25 mg/kg, intramuscular) and/or daily treatment with H. perforatum (300 mg/kg, in place of drinking water) for 7 days. Fluphenazine increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the locomotor activity. In experiment 2, rats received reserpine every 2 days for 6 days (0.5 mg/kg, subcutaneous) and/or H. perforatum (300 mg/kg, in place of drinking water) daily for 16 days beginning 10 days before the first administration of reserpine. Reserpine treatment increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the number of rears but did prevent the effect of reserpine on the number of crossings. In conclusion, H. perforatum failed to protect against orofacial movements induced by fluphenazine or reserpine in rats.

Ex vivo and in vitro inhibitory potential of Kava extract on monoamine oxidase B activity in mice.

Background and aim: This study investigated the effect of Kava extract (Piper methysticum), a medicinal plant that has been worldly used by its anxiolytic effects, on monoamine oxidase (MAO) activity of mice brain after 21 days of treatment as well as anxiolytic and locomotor behavior. Furthermore, the in vitro inhibitory profile of Kava extract on MAO-B activity of mouse brain was evaluated. Experimental procedure: Mice were treated with Kava extract (10, 40, 100 and 400 mg/kg) for 21 days by gavage. After behavioral analysis (plus maze test and open field), MAO activity in different mouse brain structures (cortex, hippocampus, region containing the substantia nigra and striatum) were performed. MAO-B inhibitory profile was characterized in vitro. Results: The treatment with Kava extract (40 mg/kg) increased the percentage of entries of mice into the open arms. Ex vivo analysis showed an inhibition on MAO-B activity caused by Kava extract in cortex (10 mg/kg) and in the region containing the substantia nigra (10 and 100 mg/kg). In vitro, Kava extract also reversibly inhibited MAO-B activity with IC50 = 14.62 µg/mL and, increased Km values at the concentrations of 10 and 30 µg/mL and decreased Vmax value at 100 µg/mL. Conclusion: Kava extract showed different effects on MAO-B isoform depending on the brain structure evaluated. Therefore, the use of Kava extract could be promissory in pathologies where MAO-B is the pharmacological target.

Resveratrol protects against a model of vacuous chewing movements induced by reserpine in mice.

Reserpine treatment is a putative animal model of orofacial dyskinesia, tremor, and Parkinsonism. Here, we examined the effects of resveratrol, a polyphenol with neuroprotective properties primarily contained in red grapes and red wine, in an animal model of vacuous chewing movements (VCMs) induced by treatment with reserpine. Mice were treated with reserpine (1 mg/kg, subcutaneously on days 1 and 3) and/or resveratrol (5 mg/kg, intraperitoneally 3 consecutive days). VCM, locomotor, and exploratory performance were evaluated. Reserpine treatment produced an increase in VCM intensity, which was significantly reduced by resveratrol co-treatment. Reserpine also decreased locomotor and exploratory activity in the open field test. However, resveratrol co-treatment was not able to protect against these effects. The data suggest that resveratrol could be a promising pharmacological tool for studying VCM in rodents. However, further investigations are needed to understand the exact mechanisms involved in the neuroprotective effects of resveratrol.

Behavioral and neurochemical effects induced by reserpine in mice.

RATIONALE: Reserpine, a monoamine-depleting agent, which irreversibly and non-selectively blocks the vesicular monoamine transporter, has been used as an animal model to study several neurological disorders, including tardive dyskinesia and Parkinson's disease. OBJECTIVE: The purpose of this study was to examine if motor deficits induced by reserpine in mice could be related to alterations in the expression of dopaminergic system proteins such as tyrosine hydroxylase (TH) and dopamine transporter (DAT) and in the activity of monoamine oxidase (MAO). METHODS: Mice received either vehicle or reserpine (0.1, 0.5, or 1 mg/kg, s.c.) for four consecutive days. Two, 20, or 60 days after reserpine withdrawal, behavioral, and neurochemical changes were evaluated. RESULTS: Reserpine at a dose of 0.5 and 1 mg/kg increased vacuous chewing movements (VCMs) and reduced locomotion. Behavioral changes were accompanied by reduction in TH immunoreactivity in the striatum evaluated on days 2 and 20 after the last injection of 1 mg/kg reserpine. Furthermore, negative correlations were found between VCM and MAO-A or MAO-B on day 2 and TH striatal immunoreactivity on day 20 after the last injection of 1 mg/kg reserpine. A positive correlation was observed between VCMs and DAT immunoreactivity in the substantia nigra on day 2 after the last injection of 0.5 mg/kg reserpine. CONCLUSIONS: These findings suggest that the pharmacological blockage of vesicular monoamine transporter (VMAT) by reserpine caused neurochemical and behavioral alterations in mice.

Anandamide attenuates haloperidol-induced vacuous chewing movements in rats.

Antipsychotics may cause tardive dyskinesia in humans and orofacial dyskinesia in rodents. Although the dopaminergic system has been implicated in these movement disorders, which involve the basal ganglia, their underlying pathomechanisms remain unclear. CB1 cannabinoid receptors are highly expressed in the basal ganglia, and a potential role for endocannabinoids in the control of basal ganglia-related movement disorders has been proposed. Therefore, this study investigated whether CB1 receptors are involved in haloperidol-induced orofacial dyskinesia in rats. Adult male rats were treated for four weeks with haloperidol decanoate (38mg/kg, intramuscularly - i.m.). The effect of anandamide (6nmol, intracerebroventricularly - i.c.v.) and/or the CB1 receptor antagonist SR141716A (30µg, i.c.v.) on haloperidol-induced vacuous chewing movements (VCMs) was assessed 28days after the start of the haloperidol treatment. Anandamide reversed haloperidol-induced VCMs; SR141716A (30µg, i.c.v.) did not alter haloperidol-induced VCM per se but prevented the effect of anandamide on VCM in rats. These results suggest that CB1 receptors may prevent haloperidol-induced VCMs in rats, implicating CB1 receptor-mediated cannabinoid signaling in orofacial dyskinesia.

Antidepressant-like effect of Ilex paraguariensis in rats.

In this study, we investigated the possible antidepressant-like effect of I. paraguariensis in rats. Rats were treated for four weeks with an aqueous extract of I. paraguariensis in drinking water, following the traditional preparation of this beverage. After the period of treatment, behavioral (elevated plus-maze, open field test, and forced swimming test) and biochemical parameters (lipid peroxidation assay, thiol content, vitamin C levels, and monoamine oxidase activity) were evaluated. Animals were also analyzed on forced swimming test after 24 hours of I. paraguariensis intake. An additional group was injected with selegiline 24 hours and 30 minutes before forced swimming test as positive control. HPLC analysis revealed the profile of I. paraguariensis extract. I. paraguariensis reduced the immobility time on forced swimming test without significant changes in locomotor activity in the open field test. Any anxiolytic/anxiogenic effect of I. paraguariensis was observed in rats through the elevated plus-maze test. The antidepressant-like effect of I. paraguariensis was not accompanied by inhibitory effect on monoamine oxidase activity. There were no significant alterations on lipid peroxidation, thiol content, and vitamin C levels among the groups. In conclusion, aqueous extract of I. paraguariensis decreases the time of immobility in rats suggesting an antidepressant-like effect.

Effects of diphenyl diselenide on methylmercury toxicity in rats.

This study investigates the efficacy of diphenyl diselenide [(PhSe)2] in attenuating methylmercury- (MeHg-)induced toxicity in rats. Adult rats were treated with MeHg [5 mg/kg/day, intragastrically (i.g.)] and/ or (PhSe)2 [1 mg/kg/day, intraperitoneally (i.p.)] for 21 days. Body weight gain and motor deficits were evaluated prior to treatment, on treatment days 11 and 21. In addition, hepatic and cerebral mitochondrial function (reactive oxygen species (ROS) formation, total and nonprotein thiol levels, membrane potential (ΔΨm), metabolic function, and swelling), hepatic, cerebral, and muscular mercury levels, and hepatic, cerebral, and renal thioredoxin reductase (TrxR) activity were evaluated. MeHg caused hepatic and cerebral mitochondrial dysfunction and inhibited TrxR activity in liver (38,9%), brain (64,3%), and kidney (73,8%). Cotreatment with (PhSe)2 protected hepatic and cerebral mitochondrial thiols from depletion by MeHg but failed to completely reverse MeHg's effect on hepatic and cerebral mitochondrial dysfunction or hepatic, cerebral, and renal inhibition of TrxR activity. Additionally, the cotreatment with (PhSe)2 increased Hg accumulation in the liver (50,5%) and brain (49,4%) and increased the MeHg-induced motor deficits and body-weight loss. In conclusion, these results indicate that (PhSe)2 can increase Hg body burden as well as the neurotoxic effects induced by MeHg exposure in rats.

Resveratrol reduces vacuous chewing movements induced by acute treatment with fluphenazine.

Treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the possible neuroprotective effects of resveratrol, a polyphenol compound contained in red grapes and red wine, in an animal model of orofacial dyskinesia (OD) induced by acute treatment with fluphenazine. Adult male rats were treated during 3 weeks with fluphenazine enantate (25 mg/kg, i.m., single administration) and/or resveratrol (1 mg/kg, s.c., 3 times a week). Vacuous chewing movements (VCMs), locomotor and exploratory performance were evaluated. Fluphenazine treatment produced VCM in 70% of rats and the concomitant treatment with resveratrol decreased the prevalence to 30%, but did not modify the intensity of VCMs. Furthermore, the fluphenazine administration reduced the locomotor and exploratory activity of animals in the open field test. Resveratrol co-treatment was able to protect the reduction of both parameters. Taken together, our data suggest that resveratrol could be considered a potential neuroprotective agent by reducing motor disorders induced by fluphenazine treatment.