RESUMO
Parkinson's disease (PD) is a neurodegenerative disease characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compact (SNpc), with consequent depletion of dopamine in the striatum, which gives rise to the characteristic motor symptoms of PD. Although its etiology is unknown, several studies have suggested that oxidative stress plays a critical function in the pathophysiology of PD, and antioxidant agents could be helpful to slown down the dopaminergic neurodegeneration. Carvacrol (CA) is a phenolic monoterpene found in essential oils of many aromatic plants that presents antioxidant and neuroprotective effects. This study aimed to assess the effect of CA in a reserpine (RES)-induced rat model of PD. Male Wistar rats received 15â¯s.c. injections of 0.1â¯mg/kg RES or vehicle, every other day, concomitantly to daily i.p. injections of CA (12.5 or 25â¯mg/kg) or vehicle. Across the treatment, the animals were submitted to behavioral evaluation in the catalepsy test (performed daily), open field test (7th day) and assessment of vacuous chewing movements (12th, 20th and 30th days). Upon completion of behavioral tests, rats were perfused and their brains underwent tyrosine hydroxylase (TH) immunohistochemical analysis. Our results showed that CA (12.5 e 25â¯mg/kg) prevented the increase in catalepsy behavior and number of vacuous chewing movements, but failed to revert the decreased open-field locomotor activity induced by RES. In addition, CA in both doses prevented the decrease in TH immunostaining induced by RES in the SNpc and dorsal striatum. Taken together, our results suggest that CA shows a protective effect in a rat model of PD, preventing motor and neurochemical impairments induced by RES. Thus, the use of CA as a promising new strategy for the prevention and/or treatment of PD may be considered.
Assuntos
Antiparasitários/uso terapêutico , Antipsicóticos/toxicidade , Monoterpenos/uso terapêutico , Transtornos Parkinsonianos/induzido quimicamente , Reserpina/toxicidade , Tirosina 3-Mono-Oxigenase/metabolismo , Análise de Variância , Animais , Catalepsia/diagnóstico , Catalepsia/etiologia , Cimenos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Mastigação/efeitos dos fármacos , Transtornos Parkinsonianos/fisiopatologia , Ratos , Ratos Wistar , Proteínas Vesiculares de Transporte de Monoamina/metabolismoRESUMO
All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D2 or serotonin (5-HT2A) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities. A difficulty in developing 5-HT2C agonists is that most ligands also possess 5-HT2B and/or 5-HT2A activities. We have developed selective 5-HT2C ligands and herein describe their preclinical effectiveness for treating schizophrenia-like behaviors. JJ-3-45, JJ-3-42, and JJ-5-34 reduced amphetamine-stimulated hyperlocomotion, restored amphetamine-disrupted prepulse inhibition, improved social behavior, and novel object recognition memory in NMDA receptor hypofunctioning NR1-knockdown mice, and were essentially devoid of catalepsy. However, they decreased motivation in a breakpoint assay and did not promote reversal learning in MK-801-treated mice. Somewhat similar effects were observed with lorcaserin, a 5-HT2C agonist with potent 5-HT2B and 5-HT2A agonist activities, which is approved for treating obesity. Microdialysis studies revealed that both JJ-3-42 and lorcaserin reduced dopamine efflux in the infralimbic cortex, while only JJ-3-42 decreased it in striatum. Collectively, these results provide additional evidence that 5-HT2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.
Assuntos
Inibição Pré-Pulso/efeitos dos fármacos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Estimulação Acústica/efeitos adversos , Anfetamina/toxicidade , Animais , Benzazepinas/farmacologia , Catalepsia/tratamento farmacológico , Catalepsia/etiologia , Aprendizagem por Discriminação/efeitos dos fármacos , Modelos Animais de Doenças , Interações Medicamentosas , Comportamento Exploratório/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Motivação/efeitos dos fármacos , Neurotransmissores/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Agonistas do Receptor 5-HT2 de Serotonina/química , Comportamento SocialRESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The present study was undertaken to investigate the pretreatment effects of standardized Ginkgo biloba extract (EGb761(®)) and low-dose whole-body γ-irradiation on the neurological dysfunction in the reserpine model of PD. Male Wistar rats were pretreated orally with EGb761 or fractionated low-dose whole-body γ-irradiation or their combination, then subjected to intraperitoneal injection of reserpine (5 mg/kg body weight) 24 h after the final dose of EGb761 or radiation. Reserpine injection resulted in the depletion of striatal dopamine (DA) level, increased catalepsy score, increased oxidative stress indicated via depletion of glutathione (GSH), increased malondialdehyde (MDA) and iron levels, decreased DA metabolites metabolizing enzymes; indicated by inhibition by glutathione-S-transferase, and nicotinamide adenine dinucleotide phosphate (NADPH)-quinone oxidoreductase (NQO) activities, mitochondrial dysfunction; indicated by declined complex I activity, and adenosine triphosphate (ATP) level and increased apoptosis; indicated by decreased mitochondrial B cell lymphoma-2 (Bcl-2) protein level and by transmission electron microscope. EGb761 and low-dose γ-radiation ameliorated the reserpine-induced state of oxidative stress, mitochondrial dysfunction, and apoptosis in brain. It can be concluded that EGb761, a widely used herbal medicine and low dose of γ-irradiation have protective effects for combating Parkinsonism possibly via replenishment of GSH levels.
Assuntos
Corpo Estriado/efeitos da radiação , Suplementos Nutricionais , Neurônios/efeitos da radiação , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/prevenção & controle , Extratos Vegetais/uso terapêutico , Irradiação Corporal Total , Animais , Antiparkinsonianos/uso terapêutico , Apoptose/efeitos da radiação , Comportamento Animal/efeitos da radiação , Química Encefálica/efeitos da radiação , Catalepsia/etiologia , Catalepsia/prevenção & controle , Terapia Combinada , Corpo Estriado/metabolismo , Corpo Estriado/ultraestrutura , Modelos Animais de Doenças , Raios gama/uso terapêutico , Ginkgo biloba , Masculino , Neurônios/metabolismo , Neurônios/ultraestrutura , Estresse Oxidativo/efeitos da radiação , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Projetos Piloto , Distribuição Aleatória , Ratos Wistar , ReserpinaRESUMO
Present study focused on the evaluation of aqueous extract of Sida cordifolia (AESC), and its different fractions; hexane (HFSC), chloroform (CFSC) and aqueous (AFSC), against rotenone induced biochemical, neurochemical, histopathological and behavioral alterations in a rat model of Parkinson's disease (PD). An estimation of the level of thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and catalase (CAT) along with superoxide anion generation (SAG) in different brain regions (cortex, midbrain and cerebellum) was carried out to assess biochemical changes. Behavioral evaluation tests (catalepsy, rearing behavior and posture instability) and neurochemical estimations (norepinephrine, dopamine and serotonin level) along with histopathological evaluations of different brain regions were also performed. The varying doses (50, 100, 250mg/kg; p.o.) of different test treatments (AESC, HFSC, CFSC and AFSC) were co-administered along with rotenone (2mg/kg; s.c.), for a period of 35 days to rats of various groups and compared with rotenone per se (negative control) and l-deprenyl (positive control; 10mg/kg; p.o.) treated groups for the above mentioned parameters. The increase in catalepsy and posture instability along with decrease in rearing behavior observed due to rotenone treatment was significantly attenuated by co-treatment with varying doses of AESC and AFSC. Results of the histopathological studies of different brain regions of rats showed eosinophilic lesions in the mid brain region due to rotenone treatment. The eosinophilic lesions were significantly attenuated in co-treated groups of AESC-100mg/kg and AFSC-100mg/kg. Rotenone induced oxidative damage, revealed by increased level of TBARS, SAG and decreased level of GSH and CAT in mid brain region of rats, was attenuated by the co-treatment of AESC and AFSC. The rotenone induced decrease of dopamine level in the midbrain region of rats was also attenuated by co-treatment of AESC-100mg/kg and AFSC-100mg/kg. The maximum effect in all the above activities was observed in AFSC (100mg/kg) treated group, which was comparable to l-deprenyl treated group. The HFSC and CFSC co-treatment failed to show significant attenuation of rotenone induced damage. These results indicate the possible therapeutic potential of most polar fraction of AESC i.e. AFSC in PD by virtue of its antioxidative actions.
Assuntos
Inseticidas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/etiologia , Fitoterapia/métodos , Extratos Vegetais/uso terapêutico , Rotenona/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalepsia/tratamento farmacológico , Catalepsia/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Masculino , Malvaceae/química , Neurotransmissores/metabolismo , Doença de Parkinson/tratamento farmacológico , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transtornos de Sensação/tratamento farmacológico , Transtornos de Sensação/etiologia , Substâncias Reativas com Ácido TiobarbitúricoRESUMO
Freezing or catalepsy is a passive-defensive reaction to stress. The participation of brain serotonin (5-HT) in the regulation of catalepsy was shown. The major gene of predisposition to catalepsy in CBA strain was localized in a 59-70 cM fragment of chromosome 13. This fragment was transferred from the CBA strain to genome of AKR non-cataleptic strain and created AKR. CBA-D13Mit76 (D13) congenic strain. The aim of the study was to compare the effects of acute stress (restriction, 1 h) on corticosterone level in plasma, the expression of c-Fos gene (neuromarker of stress) and serotonin metabolism in the brain in AKR catalepsy-resistant strain and congenic D13 catalepsy-prone strain. The level of corticosterone was significantly lower (p < 0.001) in the stressed D13 mice compared with the stressed AKR mice. Acute stress led to increased expression of c-Fos gene in the hypothalamus and midbrain in mice of both strains. Stress increased (p < 0.05) serotonin turnover in midbrain in D13 mice, but not in AKR. Thus, the fragment of chromosome 13, containing the major gene of catalepsy, participates in the regulation of hormonal response and serotonin turnover to acute stress.
Assuntos
Catalepsia/genética , Hipotálamo/metabolismo , Mesencéfalo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Serotonina/metabolismo , Estresse Fisiológico , Animais , Catalepsia/etiologia , Catalepsia/metabolismo , Cromossomos de Mamíferos , Corticosterona/sangue , Expressão Gênica , Predisposição Genética para Doença , Hipotálamo/fisiopatologia , Masculino , Mesencéfalo/fisiopatologia , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-fos/genética , Restrição Física/efeitos adversosRESUMO
Chronic subthalamic nucleus high frequency stimulation (STN HFS) improves motor function in Parkinson's disease. However, its efficacy on cognitive function and the mechanisms involved are less known. The aim of this study was to assess the effects of STN HFS in hemiparkinsonian awake rats performing different specific motor tests and a cognitive operant task. Unilateral STN HFS applied in unilaterally DA-depleted rats decreased the apomorphine-induced circling behaviour and reduced catalepsy induced by the neuroleptic haloperidol. DA-depleted rats exhibited severe deficits in the operant task, among which the inability to perform the task was not alleviated by STN HFS. However, in a few animals showing less impairment, STN HFS significantly reduced the contralateral neglect induced by the lesion. These results are the first to demonstrate a beneficial effect of STN HFS applied in awake rats on basic motor functions. However, STN HFS appears to be less effective on impaired cognitive functions.
Assuntos
Condicionamento Operante/fisiologia , Terapia por Estimulação Elétrica , Atividade Motora/fisiologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Núcleo Subtalâmico/fisiologia , Adrenérgicos/farmacologia , Animais , Antidiscinéticos/efeitos adversos , Antiparkinsonianos/efeitos adversos , Apomorfina/efeitos adversos , Catalepsia/etiologia , Comportamento de Escolha/fisiologia , Cognição/fisiologia , Lateralidade Funcional , Haloperidol/efeitos adversos , Masculino , Modelos Animais , Oxidopamina/farmacologia , Ratos , Ratos Long-Evans , Tempo de Reação/fisiologia , Núcleo Subtalâmico/patologiaRESUMO
Experimental evidence in canine narcolepsy suggests that central cholinergic systems are critically involved in the regulation of cataplexy, an abnormal manifestation of REM sleep atonia. In the current study, we found that intracerebroventricular perfusion of methyl-B12, (10(-5)-10(-2) M), significantly aggravated cataplexy and enhanced REM sleep in narcoleptic dogs. Choline, a direct precursor of acetylcholine, was also found to aggravate cataplexy, while cyano-B12, a vitamin B12 analog without methyl donating abilities, had no effect on cataplexy. Since both methyl-B12 and choline are reported to enhance acetylcholine synthesis, enhancement of the biosynthesis of acetylcholine may be involved in the effects observed in canine narcolepsy. Our results suggest that central administration of methyl-B12 has the potential to modulate both normal and pathological REM sleep.