RESUMO
Parkinson's disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects of aminophylline, a non-selective adenosine A1 and A2A receptor antagonist, on catalepsy and gait in a haloperidol-induced PD model. Sixty adult male Swiss mice were surgically implanted with guide cannulas that targeted the basal ganglia. After seven days, the mice received intraperitoneal injections of either haloperidol (experimental group, PD-induced model) or saline solution (control group, non-PD-induced model), followed by intracerebral infusions of aminophylline. The assessments included catalepsy testing on the bar and gait analysis using the Open Field Maze. A two-way repeated-measures analysis of variance (ANOVA), followed by Tukey's post hoc tests, was employed to evaluate the impact of groups (experimental × control), aminophylline (60 nM × 120 nM × saline/placebo), and interactions. Significance was set at 5%. The results revealed that the systemic administration of haloperidol in the experimental group increased catalepsy and dysfunction of gait that paralleled the observations in PD. Co-treatment with aminophylline at 60 nM and 120 nM reversed catalepsy in the experimental group but did not restore the normal gait pattern of the animals. In the non-PD induced group, which did not present any signs of catalepsy or motor dysfunctions, the intracerebral dose of aminophylline did not exert any interference on reaction time for catalepsy but increased walking distance in the Open Field Maze. Considering the results, this study highlights important adenosine interactions in the basal ganglia of animals with and without signs comparable to those of PD. These findings offer valuable insights into the neurobiology of PD and emphasize the importance of exploring novel therapeutic strategies to improve patient's catalepsy and gait.
Assuntos
Aminofilina , Catalepsia , Modelos Animais de Doenças , Marcha , Haloperidol , Doença de Parkinson , Animais , Catalepsia/tratamento farmacológico , Catalepsia/induzido quimicamente , Camundongos , Masculino , Aminofilina/administração & dosagem , Aminofilina/farmacologia , Aminofilina/uso terapêutico , Marcha/efeitos dos fármacos , Haloperidol/administração & dosagem , Haloperidol/farmacologia , Doença de Parkinson/tratamento farmacológicoRESUMO
Parkinson's disease is a degenerative, chronic and progressive disease, characterized by motor dysfunctions. Patients also exhibit non-motor symptoms, such as affective and sleep disorders. Sleep disorders can potentiate clinical and neuropathological features and lead to worse prognosis. The goal of this study was to evaluate the effects of sleep deprivation (SD) in mice submitted to a progressive pharmacological model of Parkinsonism (chronic administration with a low dose of reserpine). Male Swiss mice received 20 injections of reserpine (0.1 mg/kg) or vehicle, on alternate days. SD was applied before or during reserpine treatment and was performed by gentle handling for 6 h per day for 10 consecutive days. Animals were submitted to motor and non-motor behavioral assessments and neurochemical evaluations. Locomotion was increased by SD and decreased by reserpine treatment. SD during treatment delayed the onset of catalepsy, but SD prior to treatment potentiated reserpine-induced catalepsy. Thus, although SD induced an apparent beneficial effect on motor parameters, a delayed deleterious effect on alterations induced by reserpine was found. In the object recognition test, both SD and reserpine treatment produced cognitive deficits. In addition, the association between SD and reserpine induced anhedonic-like behavior. Finally, an increase in oxidative stress was found in hippocampus of mice subjected to SD, and tyrosine hydroxylase immunoreactivity was reduced in substantia nigra of reserpine-treated animals. Results point to a possible late effect of SD, aggravating the deficits in mice submitted to the reserpine progressive model of PD.
Assuntos
Modelos Animais de Doenças , Transtornos Parkinsonianos , Reserpina , Privação do Sono , Animais , Masculino , Reserpina/farmacologia , Privação do Sono/complicações , Camundongos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Catalepsia/induzido quimicamente , Estresse Oxidativo/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , Atividade Motora/fisiologia , Atividade Motora/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Anedonia/fisiologia , Anedonia/efeitos dos fármacosRESUMO
BACKGROUND: Haloperidol (HAL) is an antipsychotic used in the treatment of schizophrenia. However, adverse effects are observed in the extrapyramidal tracts due to its systemic action. Natural compounds are among the treatment alternatives widely available in Brazilian biodiversity. Mygalin (MY), a polyamine that was synthesized from a natural molecule present in the hemolymph of the Acanthoscurria gomesian spider, may present an interesting approach. AIMS: This study aimed to evaluate the effect of MY in mice subjected to HAL-induced catalepsy. METHODS: Male Swiss mice were used. Catalepsy was induced by intraperitoneal administration of HAL (0.5 mg/kg - 1 mL/Kg) diluted in physiological saline. To assess the MY effects on catalepsy, mice were assigned to 4 groups: (1) physiological saline (NaCl 0.9 %); (2) MY at 0.002 mg/Kg; (3) MY at 0.02 mg/Kg; (4) MY at 0.2 mg/Kg. MY or saline was administered intraperitoneally (IP) 10 min b HAL before saline. Catalepsy was evaluated using the bar test at 15, 30, 60, 90, and 120 min after the IP administration of HAL. RESULTS: The latency time in the bar test 15, 30, 60, and 90 min increased (p < 0.05) after IP administration of HAL compared to the control group. Catalepsy was attenuated 15, 30, 90, and 120 min (p < 0.05) after the IP-administration of MY at 0.2 mg/Kg; while MY at 0.02 mg/Kg attenuated catalepsy 15 min after the HAL treatment. Our findings showed that MY attenuates the HAL-induced cataleptic state in mice.
Assuntos
Antipsicóticos , Aranhas , Camundongos , Masculino , Animais , Haloperidol/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Antipsicóticos/efeitos adversosRESUMO
Several useful animal models for parkinsonism have been developed so far. Haloperidol-induced catalepsy is often used as a rodent model for the study of motor impairments observed in Parkinson's disease and related disorders and for the screening of potential antiparkinsonian compounds. The objective of this systematic review is to identify publications that used the haloperidol-induced catalepsy model for parkinsonism and to explore the methodological characteristics and the main questions addressed in these studies. A careful systematic search of the literature was carried out by accessing articles in three different databases: Web of Science, PubMed and SCOPUS. The selection and inclusion of studies were performed based on the abstract and, subsequently, on full-text analysis. Data extraction included the objective of the study, study design and outcome of interest. Two hundred and fifty-five articles were included in the review. Publication years ranged from 1981 to 2020. Most studies used the model to explore the effects of potential treatments for parkinsonism. Although the methodological characteristics used are quite varied, most studies used Wistar rats as experimental subjects. The most frequent dose of haloperidol used was 1.0 mg/kg, and the horizontal bar test was the most used to assess catalepsy. The data presented here provide a framework for an evidence-based approach to the design of preclinical research on parkinsonism using the haloperidol-induced catalepsy model. This model has been used routinely and successfully and is likely to continue to play a critical role in the ongoing search for the next generation of therapeutic interventions for parkinsonism.
Assuntos
Catalepsia , Transtornos Parkinsonianos , Animais , Catalepsia/induzido quimicamente , Modelos Animais de Doenças , Haloperidol/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Ratos , Ratos WistarRESUMO
INTRODUCTION: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. OBJECTIVE: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. MATERIALS AND METHODS: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. RESULTS: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. CONCLUSION: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.
Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.
Assuntos
Antiparkinsonianos/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Animais , Antiparkinsonianos/administração & dosagem , Carbidopa/administração & dosagem , Catalepsia/induzido quimicamente , Cumarínicos , Modelos Animais de Doenças , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Haloperidol , Levodopa/administração & dosagem , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Inibidores da Monoaminoxidase/administração & dosagem , Doença de Parkinson Secundária/induzido quimicamente , Reserpina/administração & dosagemRESUMO
Abstract Introduction: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.
Resumen Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo [3,2-g ] chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.
Assuntos
Animais , Masculino , Camundongos , Doença de Parkinson Secundária/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Antiparkinsonianos/uso terapêutico , Doença de Parkinson Secundária/induzido quimicamente , Reserpina/administração & dosagem , Carbidopa/administração & dosagem , Catalepsia/induzido quimicamente , Levodopa/administração & dosagem , Cumarínicos , Modelos Animais de Doenças , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Haloperidol , Locomoção/efeitos dos fármacos , Camundongos Endogâmicos ICR , Inibidores da Monoaminoxidase/administração & dosagem , Antiparkinsonianos/administração & dosagemRESUMO
Chronic use of typical antipsychotic haloperidolis related to movement disturbances such as parkinsonism, akathisia and tardive dyskinesia which have been related to excitotoxicity in extrapyramidal brain areas, requiring their prevention and treatment. In the current study we evaluated the influence of the magnesium on prevention (for 28days before-), reversion (for 12days after-) and concomitant supplementation on haloperidol-induced movement disorders in rats. Sub-chronic haloperidol was related to orofacial dyskinesia (OD) and catalepsy development, increased generation of reactive species (RS) and levels of protein carbonyl (PC) in cortex, striatum and substantia nigra (SN) in all experimental protocols. When provided preventatively, Mg reduced the increase of OD and catalepsy time 14 and 7days after haloperidol administration, respectively. When supplemented after haloperidol-induced OD establishment, Mg reversed this behavior after 12days, while catalepsy was reversed after 6days of Mg supplementation.When Mg was concomitantly supplemented with haloperidol administration, OD and catalepsy were prevented. Moreover, Mg supplementation was able to prevent the RS generation in both cortex and SN, reducing PC levels in all brain areas evaluated. When supplemented after haloperidol, Mg reversed RS generation in cortex and striatum, decreasing PC levels in SN and striatum.The co-administration of haloperidol and Mg supplementation prevented RS generation in cortex, striatum and SN, and PC levels in the SN.These outcomes indicate that Mg supplementation may be a useful alternative to prevent movement disturbances resulting of classic antipsychotic pharmacotherapy as haloperidol.
Assuntos
Antipsicóticos/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Discinesias/tratamento farmacológico , Haloperidol/farmacologia , Magnésio/farmacologia , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Embrião de Galinha , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Discinesias/etiologia , Haloperidol/administração & dosagem , Masculino , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
This study aims to investigate whether the egg white hydrolysate (EWH) acts on the neuropathic disorders associated with long-term Mercury (Hg) exposure in rats. 8- week-old male Wistar rats were treated for 60 days with: a) Control - saline solution (i.m.); b) Mercury - HgCl2 (1st dose 4.6µg/kg, subsequent doses 0.07µg/kg/day, i.m.); c) Hydrolysate - EWH (1g/kg/day, gavage); d) Mercury and Hydrolysate. Mechanical allodynia was assessed using Von Frey Hairs test; heat hyperalgesia by the plantar test; catalepsy by a modification of the "ring test" and spontaneous locomotor activity by a photocell activity chambers. Analyses were performed at 0, 30 and 60 days of treatment. Brain and plasma MDA, plasma NPSH and TNF-α determination and skin immunohistochemistry were performed at 60 days. Hg induced a reduction in mechanical sensitivity threshold at 30 and 60 days and in thermal sensitivity threshold at 60 days. At the end of treatment catalepsy was developed, but there was not significant alteration in spontaneous locomotor activity. Hg also increased brain and plasma MDA, plasma NPSH and TNF-α levels and the number of Merkel cell-neurite complex in the skin. EWH prevented the development of mechanical allodynia, thermal hyperalgesia and catalepsy induced by Hg and the increase in MDA concentration in brain and plasma and in the number of Merkel cell-neurite complex in the skin. In conclusion, EWH promotes neuroprotection against the toxic effects caused by Hg, demonstrating a beneficial therapeutic potential.
Assuntos
Mercúrio/toxicidade , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/complicações , Hidrolisados de Proteína/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalepsia/induzido quimicamente , Catalepsia/etiologia , Catalepsia/prevenção & controle , Clara de Ovo/química , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Hiperalgesia/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Células de Merkel/metabolismo , Neuritos/metabolismo , Hidrolisados de Proteína/isolamento & purificação , Ratos , Ratos Wistar , Pele/metabolismo , Pele/patologiaRESUMO
Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects.
Assuntos
Apomorfina/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Condicionamento Clássico/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Análise de Variância , Animais , Catalepsia/metabolismo , Condicionamento Clássico/fisiologia , Modelos Animais de Doenças , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Masculino , Ratos WistarRESUMO
Pyrrolizidine alkaloids (PAs) are toxins that are exclusively biosynthesized by plants and are commonly present in foods and herbs. PAs are usually associated with poisoning events in livestock and human beings. The aim of the present study was to evaluate the behavioral and neurochemical effects of prenatal exposure to PA integerrimine N-oxide of rats in adulthood. Pregnant Wistar rats received integerrimine N-oxide from the butanolic residue of Senecio brasiliensis by gavage on gestational days 6-20 at doses of 3, 6 and 9 mg/kg. During adulthood of the offspring, the following behavioral tests were performed: open-field, plus-maze, forced swimming, catalepsy and stereotypy. Histological analyses and monoamine levels were measured. Male offspring from dams that were exposed to 9 mg/kg showed an increase in locomotion in the open-field test, an increased frequency of entries and time spent in open arms in elevated plus-maze test, as well as decreased swimming time. In the female offspring from dams that were exposed to 9 mg/kg, there was an increased time of climbing in forced swimming and intensity of stereotyped behavior. The histological study indicates an increase in the number of multinucleated cells in the liver (6 and 9 mg/kg). In neurotransmitter analysis, specifically in the striatum, we observed change in dopamine and serotonin levels in the middle dose. Thus, our results indicate that prenatal exposure to integerrimine N-oxide changed behavior in adulthood and neurotransmitter levels in the striatum. Our results agree with previous studies, which showed that integerrimine N-oxide impaired physical and neurobehavioral development in childhood that can persist until adulthood.