RESUMO
The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.
Assuntos
Benzazepinas/farmacologia , Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Racloprida/farmacologia , Animais , Catalepsia/fisiopatologia , Corpo Estriado/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologiaRESUMO
In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 µg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.
Assuntos
Anfetamina/farmacologia , Apomorfina/farmacologia , Arginina/farmacologia , Catalepsia , Maleato de Dizocilpina/farmacologia , Dopaminérgicos/farmacologia , Inibidores Enzimáticos/farmacologia , Haloperidol/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase , Fragmentos de Peptídeos/farmacologia , Proteínas/farmacologia , Esquizofrenia , Anfetamina/administração & dosagem , Animais , Apomorfina/administração & dosagem , Arginina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Catalepsia/fisiopatologia , Modelos Animais de Doenças , Maleato de Dizocilpina/administração & dosagem , Dopaminérgicos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Haloperidol/administração & dosagem , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , Proteínas/administração & dosagem , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologiaRESUMO
Deep brain stimulation (DBS) of the colliculus inferior (IC) improves haloperidol-induced catalepsy and induces paradoxal kinesia in rats. Since the IC is part of the brain aversive system, DBS of this structure has long been related to aversive behavior in rats limiting its clinical use. This study aimed to improve intracollicular DBS parameters in order to avoid anxiogenic side effects while preserving motor improvements in rats. Catalepsy was induced by systemic haloperidol (0.5mg/kg) and after 60 min the bar test was performed during which a given rat received continuous (5 min, with or without pre-stimulation) or intermittent (5 x 1 min) DBS (30Hz, 200-600µA, pulse width 100µs). Only continuous DBS with pre-stimulation reduced catalepsy time. The rats were also submitted to the elevated plus maze (EPM) test and received either continuous stimulation with or without pre-stimulation, or sham treatment. Only rats receiving continuous DBS with pre-stimulation increased the time spent and the number of entries into the open arms of the EPM suggesting an anxiolytic effect. The present intracollicular DBS parameters induced motor improvements without any evidence of aversive behavior, pointing to the IC as an alternative DBS target to induce paradoxical kinesia improving motor deficits in parkinsonian patients.
Assuntos
Ansiedade/terapia , Catalepsia/terapia , Estimulação Encefálica Profunda/métodos , Animais , Ansiedade/induzido quimicamente , Ansiedade/fisiopatologia , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Modelos Animais de Doenças , Haloperidol/toxicidade , Masculino , Ratos , Ratos WistarRESUMO
Dual target ligands are a promising concept for the treatment of Parkinson's disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H3R (hH3R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH3R affinities with Ki values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH3R: Ki = 38 nM and hMAO B: IC50 = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight.
Assuntos
Aminas/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Aminas/química , Animais , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Catalepsia/prevenção & controle , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Haloperidol , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Cinética , Ligantes , Masculino , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Doença de Parkinson/fisiopatologia , Doença de Parkinson/prevenção & controle , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
PURPOSE: Parkinson's disease (PD) is a neurodegenerative disorder with progressive motor defects. Therefore, the aim of the present investigation was to examine whether catalepsy, asymmetry, and nociceptive behaviors; the Nissl-body and neuron distribution; brain-derived neurotrophic factor (BDNF); malondialdehyde (MDA); total antioxidant capacity (TAC) levels; and the percentage of dopamine depletion of striatal neurons in the rat model of Parkinson's disease (PD) can be affected by Toxoplasma gondii (TG) infection. METHODS: Fifty rats were divided into five groups: control (intact rats), sham (rats which received an intrastriatal injection of artificial cerebrospinal fluid (ACSF)), PD control (induction of PD without TG infection), TG control (rats infected by TG without PD induction), and PD infected (third week after PD induction, infection by TG was done). PD was induced by the unilateral intrastriatal microinjection of 6-hydroxydopamine (6-OHDA) and ELISA quantified dopamine, BDNF, MDA, and TAC in the striatum tissue. Cataleptic, asymmetrical, nociceptive, and histological alterations were determined by bar test, elevated body swing test, formalin test, and Nissl-body and neuron counting in the striatal neurons. RESULTS: The results demonstrated that PD could significantly increase the number of biased swings, descent latency time, and nociceptive behavior and decrease the distribution of Nissl-stained neurons compared to the control and sham groups. TG infection significantly improved biased swing, descent latency time, nociceptive behavior, and the Nissl-body distribution in striatal neurons in comparison to the PD control group. The striatal level of BDNF in the PD-infected and TG control groups significantly increased relative to the PD control group. The striatal MDA was significantly higher in the PD control than other groups, while striatal TAC was significantly lower in the PD control than other groups. CONCLUSIONS: The current study indicates that TG infection could improve the cataleptic, asymmetric, nociceptive and behaviors; the level of striatal dopamine release; BDNF levels; TAC; and MDA in PD rats.
Assuntos
Comportamento Animal/fisiologia , Doença de Parkinson , Toxoplasmose , Animais , Química Encefálica , Catalepsia/fisiopatologia , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Corpo Estriado/parasitologia , Corpo Estriado/patologia , Modelos Animais de Doenças , Dopamina/metabolismo , Masculino , Neurônios/citologia , Nociceptividade/fisiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/parasitologia , Doença de Parkinson/fisiopatologia , Ratos , Ratos Sprague-Dawley , Toxoplasmose/metabolismo , Toxoplasmose/fisiopatologiaRESUMO
We determined anti-Parkinson's activity of M. chamomilla L. tea in chlorpromazine (CPZ) developed investigational animal model. In this research, effects of M. chamomilla L. tea 2.14ml/ kg P.O were studied on cataleptic behavior and its effect on brain histopathological changes and immunohistochemistry (IHC) in rats. The experimental design was developed by administering CPZ (3mg/kg, I/P) for twenty-one days to produce Parkinson's disease-like symptoms to 4 animal groups. We observed that chlorpromazine significantly produced motor dysfunctions (catalepsy) in a time period of twenty-one days. The M. chamomilla L. significantly (P<0.005) minimized/shorten/taper down catalepsy in rats just like standard group (Levodopa/carbidopa treated group). The maximum reduction was observed from both treated and standard groups on the 21st day. M. chamomilla L. treated rats mid brain sections showed presence of proliferative blood vessels, increase cellularity with reactive glial cells as compared to CPZ group. Furthermore, immunostaining CD68 & CD21 of M. chamomilla L. treated rats mid brain region showed few CD68 cells & no polymorphs neutrophils after CD21 staining. Thus, this research work disclosed the neuroprotective effect of M. chamomilla L. tea against Parkinson's disease-like symptoms or anti-Parkinson's activity induced by CPZ.
Assuntos
Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Catalepsia/prevenção & controle , Matricaria , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Antiparkinsonianos/isolamento & purificação , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Catalepsia/induzido quimicamente , Catalepsia/patologia , Catalepsia/fisiopatologia , Clorpromazina , Modelos Animais de Doenças , Masculino , Matricaria/química , Fármacos Neuroprotetores/isolamento & purificação , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Extratos Vegetais/isolamento & purificação , Ratos WistarRESUMO
Phenotypical study was carried out in rats with pendulum movements. The animals exhibited a high level of abortive seizures in response to audiogenic stimuli and longer postictal catalepsy in comparison with those in Wistar population. Seizure severity positively correlated with the duration of poststimulus catalepsy (r=0.90). High aggressiveness towards humans, the absence of BP elevation in stress, lower body weights, and lower weights of the kidneys and spleen in PM rats are considered concomitant traits. Correlations were detected between startle-1 and BP in rats with pendulum movements (r=0.70) and between startle-10 and BP in narcotized Wistar rats (r=-0.0.71). The newly described signs in rats with pendulum movements did not contradict the signs of the focal seizure model with typical automatisms in humans.
Assuntos
Automatismo/fisiopatologia , Reflexo de Sobressalto/fisiologia , Convulsões/patologia , Estimulação Acústica , Animais , Pressão Sanguínea/fisiologia , Catalepsia/fisiopatologia , Rim/fisiopatologia , Movimento/fisiologia , Ratos , Ratos Wistar , Baço/fisiopatologiaRESUMO
Catalepsy - an immobile state in which individuals fail to change imposed postures - can be induced by haloperidol. In rats, the pattern of haloperidol-induced catalepsy is very similar to that observed in Parkinson's disease (PD). As some PD symptoms seem to depend on the patient's emotional state, and as anxiety disorders are common in PD, it is possible that the central mechanisms regulating emotional and cataleptic states interplay. Previously, we showed that haloperidol impaired contextual-induced alarm calls in rats, without affecting footshock-evoked calls. Here, we evaluated the influence of distinct aversive stimulations on the haloperidol-induced catalepsy. First, male Wistar rats were subjected to catalepsy tests to establish a baseline state after haloperidol or saline administration. Next, distinct cohorts were exposed to open-field; elevated plus-maze; open-arm confinement; inescapable footshocks; contextual conditioned fear; or corticosterone administration. Subsequently, catalepsy tests were performed again. Haloperidol-induced catalepsy was verified in all drug-treated animals. Exposure to open-field, elevated plus-maze, open-arm confinement, footshocks, or administration of corticosterone had no significant effect on haloperidol-induced catalepsy. Contextual conditioned fear, which is supposed to promote a more intense fear, increased catalepsy over time. Our findings suggest that only specific defensive circuitries modulate the nigrostriatal system mediating the haloperidol-induced cataleptic state.
Assuntos
Afeto/efeitos dos fármacos , Catalepsia/fisiopatologia , Medo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Masculino , Doença de Parkinson/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: The root extract of Albizia zygia (DC.) J.F. Macbr. (Leguminosae) is used to manage mental disorders in African traditional medicine. However, its value, particularly, against negative and cognitive symptoms of schizophrenia have not been evaluated. AIM: The aim of this study was to evaluate the antipsychotic properties of the hydroethanolic root extract of Albizia zygia (AZE) against positive, negative and cognitive symptoms of schizophrenia in animal models. MATERIALS AND METHODS: The effects of AZE (30-300â¯mgâ¯kg-1) were evaluated against apomorphine-induced cage climbing as well as ketamine -induced hyperlocomotion, -enhanced immobility, -impaired social interaction and novel object recognition. The propensity of AZE to induce catalepsy and to attenuate haloperidol-induced catalepsy were also investigated. RESULTS: AZE 30-300â¯mgâ¯kg-1 significantly reduced apomorphine-induced climbing behaviour as well as ketamine-induced hyperlocomotion, immobility and object recognition deficits (at least Pâ¯<â¯0.05). Moreover, the extract showed no cataleptic effect but significantly inhibited haloperidol-induced catalepsy at a dose of 30â¯mgâ¯kg-1 (Pâ¯<â¯0.05). CONCLUSION: The root extract of Albizia zygia exhibited an antipsychotic-like activity in mice with potential to alleviate positive, negative and cognitive symptoms of schizophrenia.
Assuntos
Albizzia , Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Raízes de Plantas , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Albizzia/química , Animais , Antipsicóticos/isolamento & purificação , Antipsicóticos/toxicidade , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Catalepsia/prevenção & controle , Catalepsia/psicologia , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Haloperidol , Masculino , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Raízes de Plantas/química , Plantas Medicinais , Esquizofrenia/fisiopatologia , Comportamento SocialRESUMO
Total sleep deprivation (SD) has been found to mitigate motor dysfunctions in Parkinson's disease. Apparently, the similar sensitivity of an animal model for parkinsonism would support the model's validity. Recently, we described catalepsy induced in Wistar rats by somatostatin antagonist, cyclosomatostatin (cSST); this model simulates such a disease-associated abnormality as a fall in brain somatostatin levels. To evaluate the similarity between the cSST model and Parkinson's disease, we assessed here the responsiveness of cSST-induced catalepsy to 1-h and 3-h SD. In parallel, the influence of SD on catalepsy induced by a dopamine receptor antagonist, haloperidol, was examined. It was found that the short-term SD failed to influence cataleptic responses of both types (sleep deprived rats and undisturbed ones displayed a similar duration of immobility, pâ¯>â¯0.05). By contrast, 3-h SD suppressed (pâ¯<â¯0.01) cSST-induced catalepsy, however, enhanced (pâ¯<â¯0.01) cataleptic response to haloperidol. Thus, the anti-cataleptic effect of SD appears to be cSST-specific. These findings support the validity of the cSST-induced catalepsy in Wistar rats as a model for parkinsonian motor dysfunctions.
Assuntos
Catalepsia/induzido quimicamente , Catalepsia/terapia , Antagonistas de Dopamina/toxicidade , Haloperidol/toxicidade , Peptídeos Cíclicos/toxicidade , Privação do Sono , Animais , Antipsicóticos/toxicidade , Catalepsia/fisiopatologia , Imobilização/métodos , Injeções Intraventriculares , Masculino , Ratos , Ratos Wistar , Privação do Sono/fisiopatologiaRESUMO
Narcolepsy is a sleep disorder caused by the loss of orexin (hypocretin)-producing neurons and marked by excessive daytime sleepiness and a sudden weakening of muscle tone, or cataplexy, often triggered by strong emotions. In a mouse model for narcolepsy, we previously demonstrated that serotonin neurons of the dorsal raphe nucleus (DRN) mediate the suppression of cataplexy-like episodes (CLEs) by orexin neurons. Using an optogenetic tool, in this paper we show that the acute activation of DRN serotonin neuron terminals in the amygdala, but not in nuclei involved in regulating rapid eye-movement sleep and atonia, suppressed CLEs. Not only did stimulating serotonin nerve terminals reduce amygdala activity, but the chemogenetic inhibition of the amygdala using designer receptors exclusively activated by designer drugs also drastically decreased CLEs, whereas chemogenetic activation increased them. Moreover, the optogenetic inhibition of serotonin nerve terminals in the amygdala blocked the anticataplectic effects of orexin signaling in DRN serotonin neurons. Taken together, the results suggest that DRN serotonin neurons, as a downstream target of orexin neurons, inhibit cataplexy by reducing the activity of amygdala as a center for emotional processing.
Assuntos
Tonsila do Cerebelo , Catalepsia , Núcleo Dorsal da Rafe , Neurônios Serotoninérgicos/metabolismo , Transdução de Sinais , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Animais , Catalepsia/genética , Catalepsia/metabolismo , Catalepsia/patologia , Catalepsia/fisiopatologia , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/patologia , Núcleo Dorsal da Rafe/fisiopatologia , Movimentos Oculares , Masculino , Camundongos , Camundongos Knockout , Neurônios Serotoninérgicos/patologia , Serotonina/metabolismoRESUMO
The effects of antipsychotic drugs (APDs) on the adolescent brain are poorly understood despite a dramatic increase in prescription of these drugs in adolescents over the past twenty years. Neuronal systems continue to be remodeled during adolescence. Therefore, when given in adolescence, antipsychotic drugs (APDs) have the potential to affect this remodeling. In this study we investigated the effects of chronic 22-day risperidone treatment (1.3mg/kg/day) in both adolescent and adult rats. We examined short- and long-term changes in behaviour (catalepsy, locomotion and conditioned avoidance response (CAR)), and dopaminergic and serotonergic neurochemistry in the striatum and the nucleus accumbens. Here, we report that, both during chronic treatment and after a lengthy drug-free interval, risperidone induced a sensitised cataleptic response regardless of the age of exposure. Selectively in adolescents, risperidone-induced catalepsy was inversely correlated with striatal dopamine turnover immediately after chronic treatment. After a drug-free interval, a significant proportion of rats with prior adolescent risperidone treatment also failed to acquire CAR to a defined criterion. Our data provide evidence that the same chronic risperidone treatment regimen can induce contrasting short- and long-term neural outcomes in the adolescent and adult brains.
Assuntos
Antipsicóticos/efeitos adversos , Catalepsia/induzido quimicamente , Risperidona/efeitos adversos , Fatores Etários , Animais , Antipsicóticos/administração & dosagem , Monoaminas Biogênicas/análise , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Catalepsia/sangue , Catalepsia/metabolismo , Catalepsia/fisiopatologia , Corticosterona/sangue , Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Risperidona/administração & dosagemRESUMO
Central nervous system plays a vital role in regulation of most of biological functions which are abnormally affected in various disorders including cerebral ischemia, Alzheimer's and Parkinson's (AD and PD) worldwide. Cerebral stroke is an extremely fatal and one of the least comprehensible neurological disorders due to limited availability of prospective clinical approaches and therapeutics. Since, some endogenous peptides like thyrotropin-releasing hormone have shown substantial neuroprotective potential, hence present study evaluates the newer thyrotropin-releasing hormone (TRH) analogue L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 for its neuroprotective effects against oxygen glucose deprivation (OGD), glutamate and H2O2 induced injury in pheochromocytoma cell lines (PC-12 cells) and in-vivo ischemic injury in mice. Additionally, the treatment was further analyzed with respect to models of AD and PD in mice. Cerebral ischemia was induced by clamping both bilateral common carotid arteries for ten minutes. Treatment was administered to the mice five minute after restoration of blood supply to brain. Consequential changes in neurobehavioural, biochemical and histological parameters were assessed after a week. L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 showed significant reduction in glutamate, H2O2 and OGD -induced cell death in concentration and time dependent manner. Moreover, L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 resulted in a substantial reduction in CA1 (Cornus Ammonis 1) hippocampal neuronal cell death, inflammatory cytokines, TNF-α, IL-6 and oxidative stress in hippocampus. In addition, L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 was found to be protective in two acute models of AD and PD as well these findings demonstrate the neuroprotective potential of L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 in cerebral ischemia and other diseases, which may be mediated through reduction of excitotoxicity, oxidative stress and inflammation.
Assuntos
Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Hormônio Liberador de Tireotropina/análogos & derivados , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Catalepsia/complicações , Catalepsia/tratamento farmacológico , Catalepsia/patologia , Catalepsia/fisiopatologia , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Glucose/deficiência , Ácido Glutâmico/toxicidade , Haloperidol , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Oxigênio/toxicidade , Células PC12 , Ratos , Escopolamina , Hormônio Liberador de Tireotropina/química , Hormônio Liberador de Tireotropina/farmacologia , Hormônio Liberador de Tireotropina/uso terapêuticoRESUMO
Potential roles of natural products have been identified for preventing or treating various diseases. Our aim was to investigate the effectiveness of camel milk in an animal model of Parkinson's disease and compare it with standard treatment (levodopa + carbidopa combination). 40 Wistar albino rats weighing 200-250 gram were divided into four groups of 10 animals each. Group I was kept on water and served as normal control, group II served as negative control, treated with chlorpromazine (5mg/kg i.p.), group III was given camel milk (33ml/kg p.o) and group IV the standard combination of levodopa + carbidopa (100+10mg/kg) respectively, 30 minutes after chlorpromazine treatment. All animals were subjected to the drugs treatment for 30 days. Catalepsy was assessed by Bar test on day 21 and day 30 at 30, 60, 90 and 120 minutes interval. On 30th day animals were sacrificed and whole brains were examined for histopathological changes. The results revealed highly significant (p<0.001) anti-cataleptic effect of camel milk on day 21 and 30 in comparison to chlorpromazine. When compared with standard therapy, the results showed that anti-Parkinson's activity of camel milk was significant (p<0.01) on day 21. However, the difference in activity was non-significant on day 30. Histopathology of the brain showed that administration of camel milk reveals intact architecture with mild degenerative changes than chlorpromazine and levodopa + carbidopa treated animals. In conclusion, camel milk possesses anti-Parkinson's activity. However, its long term efficacy and safety needs to be evaluated clinically.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Camelus , Clorpromazina , Leite , Transtornos Parkinsonianos/prevenção & controle , Animais , Antiparkinsonianos/farmacologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Carbidopa/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/patologia , Catalepsia/fisiopatologia , Catalepsia/prevenção & controle , Combinação de Medicamentos , Feminino , Levodopa/farmacologia , Masculino , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/psicologia , Ratos Wistar , Fatores de TempoRESUMO
A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most-promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/farmacologia , Piperazinas/química , Receptores de Superfície Celular/metabolismo , Amidas/efeitos adversos , Amidas/farmacocinética , Animais , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Cognição/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Piperazina , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Autophagy is necessary for neuronal homeostasis and its dysfunction has been implicated in Parkinson's disease (PD) as it can exacerbate endoplasmic reticulum (ER) stress and ER stress-induced apoptosis. Quercetin is a flavonoid known for its neuroprotective and antioxidant effects. The present study investigated the protective, autophagy-modulating effects of quercetin in the rotenone rat model of PD. Rotenone was intraperitoneally injected at dose of 2 ml/kg/day for 4 weeks. Simultaneous intraperitoneal injection of quercetin was given at a dose of 50 mg/kg/day also for 4 weeks. Neurobehavioral changes were studied. Oxidative/antioxidant status, C/EBP homologous protein (CHOP), Beclin-1, and dopamine levels were assessed. DNA fragmentation and histopathological changes were evaluated. This research work revealed that quercetin significantly attenuated rotenone-induced behavioral impairment, augmented autophagy, ameliorated ER stress- induced apoptosis with attenuated oxidative stress. From the current study, quercetin can act as an autophagy enhancer in PD rat model and modulates the microenvironment that leads to neuronal death.
Assuntos
Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Catalepsia/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Quercetina/farmacologia , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Peso Corporal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/genética , Catalepsia/fisiopatologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Dopamina/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Injeções Intraperitoneais , Masculino , Estresse Oxidativo , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/fisiopatologia , Ratos , Rotenona , Transdução de Sinais , Tiorredoxina Dissulfeto Redutase/genética , Tiorredoxina Dissulfeto Redutase/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismoRESUMO
The present study was undertaken to evaluate the possible protective effect of thymoquinone on chlorpromazine induced catalepsy, locomotor activity and cerebral oxidative stress in rats. The rats were divided into four groups, each group containing eight animals. The animals were evaluated after repeated administration of chlorpromazine (CPZ) 30 min before the administration of thymoquinone (TQ) for 21 days. Catalepsy was assessed using block method whereas the locomotor activity was assessed using acceleratory rotarod and actophotometer. Markers of oxidative stress parameters (LPO, GSH, GPx, GR, GST and CAT) were evaluated in the brain of rats. The cataleptic scores were significantly increased in CPZ treated rats when compared with normal control rats. Oral administration of TQ (5 and 10 mg/kg) significantly decreased cataleptic scores when compared with chlorpromazine (CPZ) treated rats. The muscle coordination and spontaneous locomotor activity was significantly decreased in CPZ treated rats when compared with normal control rats. Treatment with TQ significantly improved the muscle coordination and spontaneous locomotor activity when compared with CPZ treated rats. TQ treated rats significantly reduced the elevated levels of lipid peroxidation (LPO), increased levels of antioxidant enzymes i.e., reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and catalase (CAT) when compared with CPZ treated rats. The results clearly suggest that supplementation with TQ can be used to preclude CPZ induced extrapyramidal side effects and may find a role in reducing the oxidative stress.
Assuntos
Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzoquinonas/farmacologia , Encéfalo/efeitos dos fármacos , Catalepsia/tratamento farmacológico , Clorpromazina , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Catalepsia/induzido quimicamente , Catalepsia/metabolismo , Catalepsia/fisiopatologia , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Ratos Wistar , Teste de Desempenho do Rota-RodRESUMO
Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease.
Assuntos
Gânglios da Base/fisiopatologia , Venenos de Abelha/farmacologia , Modelos Animais de Doenças , Atividade Motora/efeitos dos fármacos , Córtex Motor/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Animais , Gânglios da Base/efeitos dos fármacos , Venenos de Abelha/administração & dosagem , Venenos de Abelha/uso terapêutico , Catalepsia/complicações , Catalepsia/tratamento farmacológico , Catalepsia/fisiopatologia , Antagonistas de Dopamina/farmacologia , Estimulação Elétrica , Haloperidol , Masculino , Córtex Motor/efeitos dos fármacos , Oxidopamina , Doença de Parkinson/complicações , Ratos Wistar , Receptores Dopaminérgicos/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/fisiopatologiaRESUMO
Catalepsy--passive defense freezing reaction in response to the threatening stimuli. In hypertrophic form, it is a symptom of brain dysfunction. In mice, the major gene that determines predisposition to catalepsy localized in the distal fragment 111.35-116.16 m. p. n. of chromosome 13. This chromosome fragment using backcrossing was transferred from the cataleptic CBA mouse stain to the genome of catalepsy resistant mouse strain C57BL/6. It was obtained two recombinant lines C57BL6.CBA-Dl3Mit76C and C57BL6.CBA-D13Mit76B, carrying the fragment of CBA and C57BL/6, respectively. It has been shown that in C57BL6.CBA-D13Mit76C mice the number of cataleptic higher compared with the control line C57BL6.CBA-Dl3Mit76B. In tests "startle reflex reaction" and "social interaction" differences in behavior were not found. At the same time reduction of exploratory behavior in the "open field" test of C57BL6.CBA-D13Mit76C mice compared with C57BL6.CBA-D13Mit76B mice was shown. Immobility time of C57BL6.CBA-D13Mit76C mice in the "forced swimming" test was also significantly lower compared to control mice C57BL6.CBA-D13Mit76B.
Assuntos
Comportamento Animal , Catalepsia , Modelos Animais de Doenças , Animais , Catalepsia/genética , Catalepsia/patologia , Catalepsia/fisiopatologia , Feminino , Masculino , Camundongos , Camundongos TransgênicosRESUMO
Non-motor symptoms of Parkinson's disease are under-studied and therefore not well treated. Here, we investigated the role of combined depletions of dopamine, norepinephrine and/or serotonin in the manifestation of motor and non-motor deficits in the rat. Then, we studied the impact of these depletions on the efficacy of deep brain stimulation of the subthalamic nucleus (STN-DBS). We performed selective depletions of dopamine, norepinephrine and serotonin, and the behavioral effects of different combined depletions were investigated using the open field, the elevated plus maze and the forced swim test. Bilateral dopamine depletion alone induced locomotor deficits associated with anxiety and mild "depressive-like" behaviors. Although additional depletions of norepinephrine and/or serotonin did not potentiate locomotor and anxiety disorders, combined depletions of the three monoamines dramatically exacerbated "depressive-like" behavior. STN-DBS markedly reversed locomotor deficits and anxiety behavior in animals with bilateral dopamine depletion alone. However, these improvements were reduced or lost by the additional depletion of norepinephrine and/or serotonin, indicating that the depletion of these monoamines may interfere with the antiparkinsonian efficacy of STN-DBS. Furthermore, our results showed that acute STN-DBS improved "depressive-like" disorder in animals with bilateral depletion of dopamine and also in animals with combined depletions of the three monoamines, which induced severe immobility in the forced swim test. Our data highlight the key role of monoamine depletions in the pathophysiology of anxiety and depressive-like disorders and provide the first evidence of their negative consequences on the efficacy of STN-DBS upon the motor and anxiety disorders in the context of Parkinson's disease.