Presynaptic and postsynaptic actions of dextroamphetamine (DEX) were studied on dopamine (DA) sensitive neurons of the subesophageal ganglion of the garden snail Helix aspersa utilizing standard microelectrode techniques. Dextroamphetamine (5.5 × 10-7-10-4 M) produced effects on DA-sensitive neurons similar to that caused by DA (5.5 × 10-7-10-4 M). On cells excited by DA, surfused DEX (5.5 × 10-7 M) caused an excitation that could be blocked by chlorpromazine (0.5-1 × 10-6 M) or haloperidol (0.5-1 × 10-6 M). Elevating the extracellular Mg2+ from 4 to 20 mM reduced the depolarization caused by DEX from 11 to 2.5 mV without affecting the response to DA. The response remaining is attributed to a direct response to DEX on DA receptors. Surfused DEX caused an inhibition of cells inhibited by DA. Both DA and DEX effects were selectively blocked by dihydroergotamine (0.5-1 × 10-6 M). Elevating the [Mg2+] decreased the hyperpolarization caused by DEX from 11 to 3 mV without affecting the DA response. The effect of elevated magnesium in decreasing responses to surfused DEX suggests that the primary action of DEX is at the nerve terminal to cause DA release. Iontophoretic application of DEX caused minimal excitation or inhibition of DA neurons. This is attributed to the fact that DA receptors at the site of drug application are not associated with synaptic innervation. The response obtained with iontophoretically applied DEX suggest a weak direct action on DA receptors.

No description available.

<p> Schizophrenia is treated with haloperidol, an antipsychotic drug. Although highly effective in treating the positive symptoms of this disease, extrapyramidal side effects also accompany haloperidol treatment, including parkinsonism. Previous investigations revealed that dopamine receptor blockade by haloperidol was not temporally correlated with the appearance of parkinsonian side effects, which begin approximately 3 weeks after haloperidol treatment. In fact, by using tyrosine hydroxylase as a marker for dopamine, TH-immunoreactivity was significantly decreased 5 minutes after haloperidol administration and further downregulation was seen after 10 minutes. Microglial activation has also been implicated in Parkinson's disease models. Haloperidol also induces maximal microglial activation at 5 minutes after administration, with activation increasing by 2 minutes. In this respect, microglial activation may precede TH downregulation, thereby mediating the downregulation. In order to test this possibility, minocycline, a microglial inhibitor, was administered to Sprague-Dawley rats. Minocycline successfully inhibited microglial activation and showed partial protection over TH levels. Caffeine and nicotine have also been implicated as neuroprotective agents in Parkinson's disease. Epidemiological evidence has indicated that both caffeine and nicotine protect against Parkinson's disease. Therefore, caffeine and nicotine were independently tested and found to both prevent TH downregulation and inhibit microglial activation. Overall, microglial activation has been found to correlate with TH downregulation induced by haloperidol. Minocycline, nicotine and caffeine have all been found to inhibit microglial activation, preventing neurotoxicity associated with haloperidol administration. </p> / Thesis / Master of Science (MSc)

Yes / Nausea and vomiting are common symptoms in palliative care. Haloperidol is often used as an antiemetic in this context, although direct evidence supporting this practice is limited. To evaluate the efficacy and clinical use of haloperidol as an antiemetic in nonpalliative care contexts to inform practice, the authors conducted a rapid review of (i) published evidence to supplement existing systematic reviews, and (ii) practical aspects affecting the use of haloperidol including formulations and doses that are commonly available internationally. In nausea and vomiting related to cancer treatment, haloperidol was superior to control in two small studies. In postoperative nausea and vomiting (PONV), two randomized controlledtrials found treatment with haloperidol comparable to ondansetron. In palliative care, an observational study found a complete response rate of 24% with haloperidol (one in four patients) which would be consistent with a number needed to treat (NNT) of 3 to 5 derived from PONV. There remains insufficient direct evidence to definitively support the use of haloperidol for the management of nausea and vomiting in palliative care. However, generalizing evidence from other clinical contexts may have some validity.

Yes / Rationale The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. Objective The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. Methods Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for 7 days, followed by a 7-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for 7 days and were then tested in the perceptual set-shifting task. Results PCP significantly (p < 0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p < 0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). Conclusions These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCP-induced cognitive deficit.

No / Antipsychotic drug-induced side effects of weight gain and sexual dysfunction have clinical significance adversely affecting both compliance and morbidity. This study evaluated the effects of haloperidol and the atypical antipsychotic risperidone (0.1¿1.0 mg/kg) on weight gain, food and water intake, the oestrous cycle and uterine weight in female hooded Lister rats. Haloperidol and risperidone treated rats displayed marked weight gain, although only risperidone induced significant increases in food consumption over the 21-day period. Neither haloperidol nor risperidone influenced water consumption. Marked disruption of the oestrous cycle was observed in risperidone- and haloperidol-treated animals (0.5 and 1.0 mg/kg), which was supported by significantly reduced uterine weights. The findings presented here suggest that the weight gain and sexual dysfunction induced by antipsychotics may be modelled in rodents. This model may offer insight into the mechanisms involved in mediation of such side effects.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Haloperidol is a typical neuroleptic widely used in the treatment of several psychotic disorders and it remains the most prescribed antipsychotic worldwide, due to its high potency and low cost. Despite its good therapeutic efficacy, the use of this drug is related to development of serious side effects of endocrine and cognitive nature, besides movement disturbances. Of particular importance, the motor disorders may be manifested in an irreversible and disabling form, whose pathophysiology has been linked to free radical generation, oxidative stress and dopaminergic neuronal death in extrapyramidal regions. Currently, polymeric nanoparticles are important terapeutic tools in the pharmaceutical area, because they permit a vectorization and a control drug release, it increasing the therapeutic efficacy and reducing adverse side effects. In this context, the present study aimed to perform a comparative evaluation among formulations of haloperidol-loaded nanocapsules and the free drug considering to its therapeutic action and side effects in rats. Firstly, it was prepared suspensions containing nanocapsules of haloperidol whose physicochemical characterization showed that haloperidol can be satisfactory encapsulated. After a first study using a pseudo-psychosis animal model, the haloperidol nanoencapsulated formulation demonstrated qualitative and quantitative therapeutic superiority, which were observed by the higher eficacy and action duration. In relation to extrapyramidal side effects, encapsulated formulation was able to prevent and/or minimize the characteristic acute and chronic movement disturbances, frequently observed with the free drug. In order to improve the results already obtained, a new formulation containing haloperidol nanocapsules was developed from the replacement of the oily core composed of caprylic and capric triglycerides in fish oil rich in polyunsaturated fatty acids, that has been described by its neuroprotective and antiapoptotic properties. This formulation showed physicalchemical suitability and reduced side effects in relation to the free drug, showing also ability to act in the prevention of oxidative stress which was observed by lower levels of lipid peroxidation, as well as an increase of antioxidant defenses in extrapyramidal regions. A third experimental phase was developed from the preparation of a new formulation of haloperidol containing grape seed oil in place of medium chain fatty acids mentioned above, which did not reach the necessary properties for a nanoformulation, but it was included for the comparative study of different nanocapsules formulations. The nanoformulation of haloperidol containing fish oil showed higher ability to prevent the motor side effects commonly seen with the free drug, which were observed by the maintenance of cell viability and control of free radical generation. Taken together, the results of this study point favorably to the development of nanocapsules formulations containing haloperidol, characterizing a positive perpective for minimizing of motor side effects consequent to the free drug. In this sense, these formulations can reduce the disabling physical limitations that cause embarrassment, contributing to a better quality of life of psychiatric patients. / O haloperidol é um neuroléptico típico comumente utilizado no tratamento de desordens psicóticas e continua sendo o antipsicótico mais prescrito no mundo, por sua elevada potência e baixo custo. Apesar da boa eficácia terapêutica, o uso do fármaco é relacionado ao desenvolvimento de sérios efeitos adversos de natureza endócrina, cognitiva e motora. De particular importância, os distúrbios motores podem se manifestar de forma irreversível e incapacitante e sua fisiopatologia tem sido associada à geração de radicais livres, estresse oxidativo e morte neuronal dopaminérgica em regiões extrapiramidais. Atualmente, as nanopartículas poliméricas constituem uma importante ferramenta na farmacologia, pois possibilitam uma vetorização e liberação controlada de fármacos, o que pode aumentar a eficácia terapêutica e reduzir os efeitos adversos. Neste contexto, o presente estudo teve como objetivo geral fazer uma avaliação comparativa entre formulações de haloperidol nanoencapsulado e o fármaco livre, considerando sua atividade terapêutica e efeitos colaterais em ratos. Inicialmente, foram desenvolvidas suspensões contendo nanocápsulas de haloperidol, cuja caracterização físico-química mostrou que o fármaco foi satisfatoriamente nanoencapsulado. Após um primeiro estudo utilizando um modelo animal de pseudo-psicose, a formulação de haloperidol nanoencapsulado mostrou superioridade terapêutica qualitativa e quantitativa, observadas através da maior eficácia e maior tempo de ação antipsicótica. Em relação aos efeitos colaterais extrapiramidais, a formulação nanoencapsulada foi capaz de prevenir e/ou minimizar os distúrbios motores agudos e subcrônicos característicos, os quais são frequentemente observados com o fármaco livre. Com o objetivo de otimizar os resultados até então observados, foi desenvolvida uma nova formulação contendo nanocápsulas de haloperidol a partir da substituição do núcleo oleoso composto por triglicerídeos cápricos e caprílicos por óleo de peixe, o qual é rico em ácidos graxos poliinsaturados e tem sido descrito por suas propriedades neuroprotetoras e antiapoptóticas. Esta formulação mostrou adequabilidade físico-química e redução de efeitos adversos motores em relação ao fármaco livre; demonstrando também capacidade de atuar na redução do estresse oxidativo, observado através dos menores níveis de peroxidação lipídica, bem como aumento das defesas antioxidantes em regiões extrapiramidais. Uma terceira etapa experimental foi desenvolvida a partir de uma nova formulação de haloperidol contendo óleo de semente de uva em substituição aos ácidos graxos de cadeia média acima referidos, a qual não atingiu completamente as propriedades necessárias para uma nanoformulação, mas mesmo assim foi incluída no estudo comparativo entre as diferentes formulações de nanocápsulas. Neste estudo, a nanoformulação de haloperidol com óleo de peixe mostrou maior capacidade de prevenir os efeitos colaterais motores comuns com o fármaco livre, atuando na manutenção da viabilidade celular e no controle da geração de radicais livres. Tomados em conjunto, os resultados do presente estudo apontam de forma favorável quanto ao desenvolvimento de formulações de nanocápsulas contendo haloperidol, o que caracteriza uma perspectiva positiva para a minimização de efeitos adversos motores decorrentes do uso do fármaco livre. Neste sentido, estas formulações poderiam colaborar na redução das limitações físicas incapacitantes e causadoras de constrangimento frequentemente descritas, contribuindo para uma melhor qualidade de vida dos pacientes psiquiátricos.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Fatty acids (FA) from the diet play a key role in the architecture of brain membrane phospholipids, and can modify plasticity and fluidity, acting decisively in the development of cognitive and neuropsychiatric disorders. Healthy lifestyle habits include balanced diet and physical activity, which has regularly been described as a form of rehabilitation or prevention of diseases affecting the CNS. This study was initially designed to evaluate the influence of regular exercise in preventing oxidative damage commonly induced by haloperidol. Exercise prevented the development of orofacial dyskinesia (OD) and antipsychotic-induced locomotor impairments. The catalase activity was recovered in the subcortical region, preventing cortical and subcortical lipoperoxidation. Also in the subcortical region, there was a positive correlation between lipid peroxidation and the OD, concurrent with a negative correlation between catalase activity and OD. While these data reinforce the involvement of oxidative stress (OS) in the development of movement disorders, physical exercise was able to increase the activity of the dopamine transporter, thereby helping to reduce levels of the neurotransmitter in the striatum, often elevated by the antipsychotic action. In the following studies, weaned rats were supplemented with different FA (soybean oil-SO, rich in polyunsaturated FA; lard-L, rich in saturated FA; and hydrogenated vegetable fat-HVF, rich in trans fatty acids) and daily exercised in the last three months. After 15 months, the animals were assigned to experiment 1 or 2. In the first one, was evaluated anxiety behavior (elevated plus-maze), memory (Barnes-maze), and the activity of Na+K+-ATPase in the cortex and hippocampus. The HVF supplementation caused an incorporation of about 0.30% of trans FA in the rat s brain, whereas L of 0.20%, with no observed trans incorporation in SO group. This incorporation did not influence the symptoms of anxiety in HVF and L groups, but the exercise benefited the SO group, increasing their exploratory and risk behavior. A memory deficit was observed in the HVF, but reversed by physical exercise, equaling the memory acquisition of the three experimental groups. The activity of Na+K+-ATPase was lower in the cortex and hippocampus of animals treated with HVF and was not modified by exercise. In the 2nd experiment, rats supplemented with the different FA showed similar brain incorporation as described above. These animals were submitted to behavioral assessments of OD, locomotion and activity of Na+K+-ATPase and catalase in the striatum. The HVF supplementation was associated with increased OD, which was intensified by the exercise in the HVF and L groups. The locomotion was reduced in these two groups and was not modified by exercise. The catalase activity was lower in L and HVF groups, but elevated by exercise in the latter one. The different FA did not alter the Na+K+-ATPase activity, which was elevated by exercise in animals supplemented with L and SO. The brain incorporation of trans FA may be related to the motor impairments mainly observed in the HVF group, while the absent incorporation in the SO group, with the best motor performance and enzymatic activities. Taken together, the presented data suggest that healthy lifestyle habits, which include reduced intake of saturated and trans FA and the regular practice of physical activity, may be able to prevent and/or reduce the development or the consequences of neurological and neuropsychiatric disorders. / Ácidos graxos (AG) provenientes da alimentação são fundamentais na arquitetura das membranas fosfolipídicas cerebrais, e podem modificar plasticidade e fluidez, atuando de forma decisiva no desenvolvimento de patologias cognitivas e neuropsiquiátricas. Hábitos de vida saudável incluem alimentação balanceada e atividade física, cuja regularidade tem sido descrita como uma forma de prevenção ou reabilitação de doenças que afetam o SNC. Este estudo foi inicialmente designado para avaliar a influência do exercício regular na prevenção de danos oxidativos comumente induzidos por haloperidol. O exercício preveniu o desenvolvimento de discinesia orofacial (DO) e os prejuízos locomotores induzidos pelo antipsicótico. A atividade da catalase foi recuperada na região subcortical, prevenindo a lipoperoxidação cortical e subcortical. Ainda na região subcortical, houve uma correlação positiva entre a lipoperoxidação e a DO, concomitante à uma correlação negativa entre a atividade da catalase e a DO. Enquanto estes dados reforçam o envolvimento do estresse oxidativo (EO) no desenvolvimento dos distúrbios do movimento, o exercício físico foi capaz de aumentar a atividade do transportador de dopamina, contribuindo para a redução dos níveis do neurotransmissor no estriado, freqüentemente elevado por ação do antipsicótico. Na seqüencia dos estudos, ratos recém desmamados foram suplementados com diferentes AG (óleo de soja-OS, rico em AG poliinsaturados; banha de porco-BP, rico em AG saturados; e gordura vegetal hidrogenada-GVH, rico em AG trans) e exercitados diariamente nos 3 meses finais. Após 15 meses, os animais foram designados para o experimento 1 ou 2. No primeiro, avaliou-se comportamentos de ansiedade (labirinto em cruz elevado), memória (labirinto de Barnes), bem como a atividade da Na+K+-ATPase no córtex e hipocampo. A suplementação GVH causou uma incorporação de cerca de 0,30% de AG trans no cérebro dos animais, enquanto a BP de 0,20%, não sendo observada incorporação trans no grupo OS. Esta incorporação não influenciou os sintomas de ansiedade nos grupos BP e GVH, mas o exercício beneficiou o grupo OS, aumentando seu comportamento exploratório e de risco. Um déficit de memória foi observado no grupo GVH, mas revertido pelo exercício físico, igualando a aquisição de memória dos três grupos experimentais. A atividade da Na+K+-ATPase foi menor no córtex e hipocampo dos animais tratados com GVH, não sendo modificada pelo exercício. No 2º experimento, ratos suplementados com os diferentes AG apresentaram incorporação cerebral similar aos acima descritos. Estes animais foram submetidos a avaliações comportamentais de DO, locomoção e atividade das enzimas Na+K+-ATPase e catalase no estriado. A suplementação GVH foi associada ao aumento da DO, a qual foi intensificada pelo exercício nos grupos GVH e BP. A locomoção foi reduzida nestes dois grupos e não foi modificada pelo exercício. A atividade da catalase foi menor nos grupos BP e GVH, mas elevada pelo exercício neste último. Os diferentes AG não modificaram a atividade da Na+K+-ATPase, a qual foi elevada pelo exercício nos animais suplementados com OS e BP. A incorporação de AG trans nas membranas cerebrais pode estar relacionada aos prejuízos motores observados, principalmente, no grupo GVH, enquanto a ausência desta incorporação no grupo OS, ao melhor desempenho motor e atividades enzimáticas. Tomados em conjunto, os dados apresentados sugerem que hábitos de vida saudáveis, os quais incluem ingestão reduzida de AG trans e saturados e a prática regular de atividade física, podem ser capazes de prevenir e/ou reduzir o desenvolvimento ou conseqüências de desordens neurológicas e neuropsiquiátricas.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The association of haloperidol (HP) with polymeric nanocapsules causes a significant improve in therapeutic efficacy prolongs the drug time of action and reduces motor side effects in rats. However, in view of the HP toxicity on organs such as liver and kidney and besides due the lack of knowledge about the toxicity of polymeric nanocapsules, the objective of this study was to evaluate the effects of formulation containing haloperidol-loaded lipid-core nanocapsules on biochemical parameters and oxidative stress (OS) markers in the same tissues, besides DNA damage in blood. For this study, 28 rats were divided in four groups (n = 7) and treated with aqueous solution containing 5% polysorbate 80 (v/v) (C group), free haloperidol suspension (FH group), blank nanocapsules suspension (B-Nc group) and haloperidol-loaded lipid-core nanocapsules suspension (H-Nc group). All suspensions were administered in the animals (0,5 mg/kg-ip) once a day, for 28 days. The results showed that a subchronic treatment with FH increased oxidative damage evidenced by the elevation in lipid peroxidation levels and diminution in antioxidant defenses like vitamin C and superoxide dismutase enzyme, decreased cell integrity and increased plasma levels of AST and ALT enzymes. FH also caused damage to kidney, but to a lesser extent, and caused damage to blood DNA. On the other hand, rats treated with H-Nc did not present these alterations. Through this comparative study was possible evidence that H-Nc did not show subchronic toxicity in liver and kidney of animals, preserving these tissues from oxidative damage and loss of cell integrity, which were observed in animals treated with free drug. / A associação de haloperidol (HP) a nanocápsulas poliméricas proporciona uma significante melhora na eficácia terapêutica, prolonga o tempo de ação e reduz efeitos adversos motores em ratos. No entanto, tendo em vista a toxicidade do HP sobre órgãos como fígado e rim e o pouco conhecimento sobre a toxicidade das nanocápsulas poliméricas, o objetivo deste estudo foi avaliar os efeitos da formulação contendo haloperidol nanoencapsulado sobre parâmetros bioquímicos e marcadores de estresse oxidativo (EO) nestes mesmos tecidos, além do dano no DNA no sangue. Para este estudo, 28 ratos foram separados em quatro grupos experimentais (n=7) e tratados com solução aquosa contendo 5% polissorbato 80 (v/v) (grupo C), suspensão de haloperidol livre (grupo FH), suspensão de nanocápsulas branca (grupo B-Nc) e suspensão de haloperidol nanoencapsulado (grupo H-Nc). Todas as suspensões foram administradas aos animais (0,5 mg/kg-ip) uma vez por dia, durante 28 dias. Os resultados mostraram que o tratamento subcrônico com FH causou danos no fígado, evidenciado pelo aumento nos níveis de peroxidação lipídica e diminuição das defesas antioxidantes como vitamina C e superóxido dismutase, diminuição na integridade celular e aumento nos níveis plasmáticos das enzimas AST e ALT. O FH também causou danos no rim, mas em menor extensão, e causou danos ao DNA sanguíneo. Por outro lado, ratos tratados com H-Nc não apresentaram estas alterações. A partir deste estudo comparativo foi possível evidenciar que o haloperidol nanoencapsulado (H-Nc) não causou toxicidade subcrônica hepática e renal aos animais, preservando estes tecidos dos danos oxidativos e da perda da integridade celular, os quais foram observados nos animais tratados com o fármaco livre.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Schizophrenia is a psychiatric disorder that affects 1% of world population and its pharmacologic treatment consists in the use of antipsychotics. It is known that chronic treatment with classical antipsychotics, such as haloperidol, can cause motors disturbers, among which stands out the tardive dyskinesia (TD). The TD pathophysiology has been associated with oxidative stress increase in areas of the brain related to the movements control. So, studies have proposed the use of natural compounds with antioxidants properties to decrease the production of reactive species on TD or on animals models of orofacial dyskinesia (OD). Bauhinia forficata (B. forficata), a plant used on folk medicine such as hypoglycemic, and presents antioxidant properties, could be used to reduce the oxidative stress present on OD. Thus, the first aim of this study was evaluate the effect of B. forficata on in vitro lipid peroxidation induced by pro-oxidants and also, the possible protector effect on OD, through of the quantifications of vacuous chewing movements (VCM), and on locomotor and exploratory activities decrease induced by haloperidol in rats (manuscript 1). B. forficata prevented the lipid peroxidation by pro-oxidant agents nitroprusside sodium, Fe2+/EDTA and Fe2+. Furthermore, adult male rats received haloperidol (38 mg/kg) each 28 days for 16 weeks and B. forficata decoction (2.5 g/L) on the place of drinking water or water to drink everyday for 16 weeks. The haloperidol treatment increased the VCM and reduced the locomotor and exploratory activities relative to control group on open field test. B. forficata co-treatment was not able to prevent the motor alterations induced by haloperidol, as well as only partially prevented VCM in rats. On the other hand, B. forficata caused an increase on locomotor activity. These results showed that B. forficata has antioxidant potential, but this effect is associated partially to protection against VCM induced by haloperidol in rats (manuscript 1). Some studies have showed that chronic treatment with classic antipsychotics can cause metabolic side effects. B. forficata which is known on folk medicine by glycemia decrease, could prevent the metabolic side effects caused by use of antipsychotics. So, the other propound of this study was to investigate the weight gain, glycemic levels and other metabolic parameters in rats chronically treated with haloperidol and the possible effect of B. forficata on these metabolic side effects (manuscript 2). After 16 weeks of treatment, the animals treated with haloperidol showed high glycemic prevalence and high glucose levels. B. forficata co-treatment elevated glucose and triglycerides levels. No difference was observed on cholesterol, urea, creatinine, alanine aminotransferase (AST), aspartate aminotransferase (ALT) and lactate dehydrogenase (LDH). Haloperidol treatment caused weight gain and promoted a significant decrease on brain/body weight rate. In conclusion, B. forficata co-treatment and haloperidol can increase the number of hyperglycemic animals. Thus, is necessary to emphasize the importance of more toxicology studies on chronic treatment with B. forficata to avoid health implications of population. / A esquizofrenia é uma desordem psiquiátrica que atinge cerca de 1% da população mundial e seu tratamento farmacológico consiste na utilização de antipsicóticos. Sabe-se que o tratamento crônico com antipsicóticos clássicos, como o haloperidol, pode causar distúrbios motores, dentre os quais se destaca a discinesia tardia (DT). A fisiopatologia da DT tem sido associada ao aumento do estresse oxidativo em áreas do cérebro relacionadas ao controle dos movimentos. Desta forma, estudos têm proposto o uso de compostos naturais com propriedades antioxidantes para diminuir a produção de espécies reativas na DT ou em modelos animais de discinesia orofacial (DO). A Bauhinia forficata (B. forficata), uma planta utilizada na medicina popular como hipoglicemiante, e que apresenta propriedades antioxidantes, poderia ser utilizada para reduzir o estresse oxidativo presente na DO. Logo, o primeiro objetivo deste estudo foi avaliar o efeito da B. forficata na peroxidação lipídica in vitro induzida por diferentes pró-oxidantes, e também o possível efeito protetor da B. forficata na DO, através da quantificação dos movimentos de mascar no vazio (MMV), e na diminuição da atividade locomotora e exploratória induzidos por haloperidol em ratos (manuscrito 1). A B. forficata preveniu a formação de peroxidação lipídica induzida pelos agentes pró-oxidantes nitroprussiato de sódio, Fe2+/EDTA e Fe2+. Além disso, ratos adultos machos receberam haloperidol (38 mg/kg) a cada 28 dias por 16 semanas, e o decocto de B. forficata (2,5 g/L) no lugar da água de beber ou água para beber todos os dias por 16 semanas. O tratamento com o haloperidol aumentou o número de MMV, e reduziu as atividades locomotora e exploratória dos animais em relação ao grupo controle no teste do campo aberto. O co-tratamento com B. forficata não foi capaz de prevenir as alterações motoras induzidas por haloperidol, bem como preveniu apenas parcialmente os MMV em ratos. Por outro lado, a B. forficata sozinha causou um aumento na atividade locomotora. Os resultados desse estudo mostraram que a B. forficata tem potencial antioxidante, mas esse efeito está associado apenas parcialmente à proteção contra os MMV induzidos pelo haloperidol em ratos (manuscrito 1). Alguns estudos têm mostrado que o tratamento crônico com antipsicóticos clássicos pode causar efeitos colaterais metabólicos. A B. forficata, conhecida na medicina popular por diminuir a glicemia, poderia prevenir os efeitos colaterais metabólicos causados pelo uso de antipsicóticos. Assim, outra proposta deste estudo foi investigar o ganho de peso, os níveis glicêmicos e outros parâmetros metabólicos em ratos tratados cronicamente com haloperidol e o possível efeito da B. forficata nesses efeitos colaterais metabólicos (manuscrito 2). Após 16 semanas de tratamento, os animais tratados com haloperidol apresentaram alta prevalência glicêmica e altos níveis séricos de glicose. O co-tratamento com B. forficata elevou os níveis de glicose e de triglicerídeos. Nenhuma diferença foi observada nos níveis de colesterol, uréia, creatinina, alanina aminotransferase, aspartato aminotransferase (AST) e lactato desidrogenase (LDH). O tratamento com haloperidol causou aumento no ganho de peso corporal e promoveu significante diminuição na taxa peso do cérebro/corpo. Em conclusão, o co-tratamento com B. forficata e haloperidol pode aumentar o número de animais hiperglicêmicos. Assim, é necessário enfatizar a importância de mais estudos toxicológicos sobre o tratamento crônico com B. forficata para evitar implicações na saúde da população.