RESUMO
Parkinson's Disease (PD) is symptomatically managed with L-DOPA but chronic use results in L-DOPA-induced dyskinesia (LID) characterized by abnormal involuntary movements (AIMs). In LID, dopamine D3 receptors (D3R) are upregulated on D1 receptor (D1R)-bearing medium spiny neurons where the can synergistically drive downstream signaling and motor behaviors. Despite evidence implying D1R-D3R cooperativity in LID, the dyskinesiogenic role of D3R has never been directly tested. To this end, we developed a specific cre-dependent microRNA (miRNA) to irreversibly prevent D3R upregulation in D1R striatal cells. D1-Cre rats received unilateral 6-hydroxydopamine lesions. Three weeks later, rats received an adeno-associated virus expressing either D3R miRNA or a scrambled (SCR) miRNA delivered into the striatum. After 4 weeks, rats received chronic L-DOPA (6 mg/kg) or vehicle. AIMs development and motor behaviors were assayed throughout treatment. At the conclusion of the experiment, efficacy and fidelity of the miRNA strategy was analyzed using in situ hybridization (ISH). ISH analyses demonstrated that D1R+/D3R+ cells were upregulated in LID and that the selective D3R miRNA reduced D1R+/D3R+ co-expression. Importantly, silencing of D3R also significantly attenuated LID development without impacting L-DOPA efficacy or other locomotion. These data highlight a dyskinesiogenic role of D3R within D1R cells in LID and highlight aberrant D1R-D3R interactions as targets of LID management.
Assuntos
Dopaminérgicos/efeitos adversos , Discinesia Induzida por Medicamentos/genética , Discinesia Induzida por Medicamentos/prevenção & controle , Levodopa/efeitos adversos , Neostriado/patologia , Receptores de Dopamina D1/genética , Receptores de Dopamina D3/genética , Animais , Comportamento Animal , Discinesia Induzida por Medicamentos/psicologia , Feminino , Terapia Genética , Hidroxidopaminas , Masculino , MicroRNAs/genética , Neostriado/metabolismo , Desempenho Psicomotor , RatosRESUMO
Prolonged administration of Levodopa (L-dopa) therapy can generate L-dopa-induced dyskinesia (LID). Accumulating evidence indicates that hyper-activation of the dopamine D1 receptor (D1R) and the cAMP signaling cascade in the medium spiny neurons (MSNs) of the striatum are involved in LID. Previous studies have shown that striatal ß-arrestin2 overexpression significantly reduces LID severity and have indicated that ß-arrestin2 may play a causal role in the dyskinesia sensitization process. L-dopa-induced changes in the expression of signaling molecules and other proteins in the striatum were examined immunohistochemically and by western blot. A rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablate ß-arrestin2. We found that striatal overexpression of AAV-mediated ß-arrestin2 produced less severe AIMs (abnormal involuntary movements) in response to L-dopa, whereas selective deletion of ß-arrestin2 in the striatal neurons dramatically enhanced the severity of dyskinesia induced by L-dopa. Furthermore, no significant improvements in motor behavior (FFT: forelimb functional test) were seen with the inhibition or overexpression of ß-arrestin2. Finally, overexpression of ß-arrestin2 diminished L-dopa-induced D1R and phosphor-DARPP32/ERK levels. Viral deletion of ß-arrestin2 markedly enhanced the key biochemical markers in the direct pathway. We found that increased availability of ß-arrestin2 ameliorated dyskinesia severity with no influence on the anti-Parkinsonian action of L-dopa, suggesting a promising approach for controlling LID in Parkinson's disease. In addition, overexpression of ß-Arrestin2 prevented the development of LID by inhibiting G protein-dependent D1R and phosphor-DARPP32/ERK signaling in dyskinetic rats.
Assuntos
Antiparkinsonianos , Discinesia Induzida por Medicamentos/terapia , Levodopa , Neostriado/metabolismo , Doença de Parkinson Secundária/terapia , beta-Arrestina 2/biossíntese , beta-Arrestina 2/genética , Adenoviridae/genética , Animais , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Deleção de Genes , Terapia Genética , Vetores Genéticos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Neostriado/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/psicologia , Fosfoproteínas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Fatores de Transcrição/efeitos dos fármacosRESUMO
BACKGROUND: Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model. METHODS: Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control. RESULTS: Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels. CONCLUSIONS: These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.
Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/terapia , Fatores Imunológicos/uso terapêutico , Levodopa/efeitos adversos , Doença de Parkinson/complicações , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Inibidores da Angiogênese/uso terapêutico , Animais , Citocinas/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Interleucina-10/metabolismo , Masculino , Neostriado/metabolismo , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Substância Negra/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Istradefylline (KW-6002), an adenosine A2A receptor antagonist, is used adjunct with optimal doses of L-3,4-dihydroxyphenylalanine (l-DOPA) to extend on-time in Parkinson's disease (PD) patients experiencing motor fluctuations. Clinical application of istradefylline for the management of other l-DOPA-induced complications, both motor and non-motor related (i.e. dyskinesia and cognitive impairments), remains to be determined. In this study, acute effects of istradefylline (60-100 mg/kg) alone, or with optimal and sub-optimal doses of l-DOPA, were evaluated in two monkey models of PD (i) the gold-standard 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of parkinsonian and dyskinetic motor symptoms and (ii) the chronic low dose (CLD) MPTP-treated macaque model of cognitive (working memory and attentional) deficits. Behavioural analyses in l-DOPA-primed MPTP-treated macaques showed that istradefylline alone specifically alleviated postural deficits. When combined with an optimal l-DOPA treatment dose, istradefylline increased on-time, enhanced therapeutic effects on bradykinesia and locomotion, but exacerbated dyskinesia. Istradefylline treatment at specific doses with sub-optimal l-DOPA specifically alleviated bradykinesia. Cognitive assessments in CLD MPTP-treated macaques showed that the attentional and working memory deficits caused by l-DOPA were lowered after istradefylline administration. Taken together, these data support a broader clinical use of istradefylline as an adjunct treatment in PD, where specific treatment combinations can be utilised to manage various l-DOPA-induced complications, which importantly, maintain a desired anti-parkinsonian response.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/administração & dosagem , Intoxicação por MPTP/tratamento farmacológico , Purinas/administração & dosagem , Antagonistas do Receptor A2 de Adenosina/administração & dosagem , Animais , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Discinesia Induzida por Medicamentos/fisiopatologia , Discinesia Induzida por Medicamentos/psicologia , Feminino , Hipocinesia/tratamento farmacológico , Hipocinesia/fisiopatologia , Hipocinesia/psicologia , Levodopa/toxicidade , Intoxicação por MPTP/fisiopatologia , Intoxicação por MPTP/psicologia , Macaca fascicularis , Transtornos das Habilidades Motoras/tratamento farmacológico , Transtornos das Habilidades Motoras/fisiopatologia , Transtornos das Habilidades Motoras/psicologia , Resultado do TratamentoRESUMO
l-DOPA therapy in Parkinson's disease often results in side effects such as l-DOPA-induced dyskinesia (LID). Our previous studies demonstrated that defective desensitization of dopamine receptors caused by decreased expression of G protein-coupled receptor kinases (GRKs) plays a role. Overexpression of GRK6, the isoform regulating dopamine receptors, in parkinsonian rats and monkeys alleviated LID and reduced LID-associated changes in gene expression. Here we show that 2-fold lentivirus-mediated overexpression of GRK6 in the dopamine-depleted striatum in rats unilaterally lesioned with 6-hydroxydopamine ameliorated supersensitive ERK response to l-DOPA challenge caused by loss of dopamine. A somewhat stronger effect of GRK6 was observed in drug-naïve than in chronically l-DOPA-treated animals. GRK6 reduced the responsiveness of p38 MAP kinase to l-DOPA challenge rendered supersensitive by dopamine depletion. The JNK MAP kinase was unaffected by loss of dopamine, chronic or acute l-DOPA, or GRK6. Overexpressed GRK6 suppressed enhanced activity of Akt in the lesioned striatum by reducing elevated phosphorylation at its major activating residue Thr(308). Finally, GRK6 reduced accumulation of ΔFosB in the lesioned striatum, the effect that paralleled a decrease in locomotor sensitization to l-DOPA in GRK6-expressing rats. The results suggest that elevated GRK6 facilitate desensitization of DA receptors, thereby normalizing of the activity of multiple signaling pathways implicated in LID. Thus, improving the regulation of dopamine receptor function via the desensitization mechanism could be an effective way of managing LID.
Assuntos
Dopaminérgicos/farmacologia , Quinases de Receptores Acoplados a Proteína G/biossíntese , Levodopa/farmacologia , Neostriado/metabolismo , Neostriado/fisiopatologia , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Dopamina/deficiência , Discinesia Induzida por Medicamentos/psicologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neostriado/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Sprague-DawleyRESUMO
Rodents with lesion of dopaminergic pathway when receiving repeated l-3,4-dihydroxiphenylalanine (l-DOPA) treatment develop abnormal involuntary movements called dyskinesia. We demonstrated that nitric oxide synthase (NOS) inhibitors mitigate l-DOPA-induced dyskinesia in rodents. The aim of the present study was to verify if the in vivo preferential neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI) affect the expression of the transcription factor FosB/ΔFosB in the lesioned striatum, an indicator of neuronal activity associated with dyskinesia. Male Wistar rats with unilateral microinjection (medial forebrain bundle) of either the neurotoxin 6-hydroxidopamine (6-OHDA; n=4-6/group) or saline (sham; n=6/group) were provided with l-DOPA (30mg/kg plus benserazide 7.5mg/kg/day, oral gavage), once a day during 22 days. 6-OHDA-lesioned animals developed abnormal involuntary movements (AIMs) classified as axial, limb, orofacial and locomotive dyskinesia and presented FosB/ΔFosB increase in the dopamine-depleted striatum. Administration of 7-NI (30mg/kg, i.p.), 30min prior to l-DOPA reduced the severity of AIMs (≈65% for axial, limb and orofacial and 74% for locomotive AIMs scores), without interfering with the rotarod performance. Simultaneously, 7-NI attenuated the expression of FosB/ΔFosB in dopamine-depleted striatum (≈65% in medial and ≈54% in lateral striatum, bregma 0.48mm). FosB/ΔFosB expression in lateral striatum was correlated with l-DOPA-induced dyskinesia. The findings described here corroborate a new approach to the management of l-DOPA-therapy in Parkinson's disease (PD) treatment.
Assuntos
Discinesia Induzida por Medicamentos/metabolismo , Indazóis/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Antiparkinsonianos/efeitos adversos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/psicologia , Indazóis/uso terapêutico , Levodopa/efeitos adversos , Masculino , Microinjeções , Atividade Motora/efeitos dos fármacos , Oxidopamina , Ratos , Ratos WistarAssuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Doenças Cardiovasculares/induzido quimicamente , Discinesia Induzida por Medicamentos/psicologia , Transtornos do Humor/complicações , Agonistas alfa-Adrenérgicos/efeitos adversos , Agonistas alfa-Adrenérgicos/uso terapêutico , Antimaníacos/efeitos adversos , Antimaníacos/uso terapêutico , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Aripiprazol , Asma/complicações , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Dor no Peito , Criança , Família , Feminino , Guanfacina/efeitos adversos , Guanfacina/uso terapêutico , Humanos , Cloreto de Lítio/efeitos adversos , Cloreto de Lítio/uso terapêutico , Masculino , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/psicologia , Testes Neuropsicológicos , Obesidade/complicações , Paroxetina/efeitos adversos , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Polimedicação , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Agitação Psicomotora/tratamento farmacológico , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Fumar/efeitos adversos , Meio SocialRESUMO
Levodopa-induced dyskinesias (LID) belong to the most common dose-limiting adverse effects of levodopa therapy. "Peak-dose" LID occur with the maximum effect of medication, 'diphasic dyskinesias' have a "beginning- and end-of-dose" pattern, and the, "off-period dyskinesia" occur during off-periods, most frequently in the early mornings and are typically dystonic in nature. The majority of patients will have developed dyskinesias after 10 years of treatment, and about 40-50% after 5 years. Occurrence of LID appears to be related to dose and duration of treatment with levodopa and severity and duration of disease. In addition, patients with younger age of onset have been reported to have an earlier onset and higher rate of LID. The important aetiological role of non-physiological pulsatile stimulation of dopaminergic receptors is increasingly recognized and more continuous dopaminergic stimulation with the longer acting dopamine agonists has been shown to reduce and delay the onset of dyskinesias. LID may not have a significant effect on quality of life in patients with early disease or in very advanced disease stages. when often other problems arise, but in other patients they may be severely disabling. Treatment strategies to overcome LID include adjustment of timing, type and amount of dopaminergic medication, treatment with amantadine and, in treatment resistant cases, stereotactic surgery involving deep brain stimulation or lesioning procedures. A number of other pharmacological options are also being explored. Several methods for the assessment of LID are available to attempt accurate assessment of efficacy, although all of these have limitations, and further evidence on their utility if needed.
Assuntos
Gerenciamento Clínico , Discinesia Induzida por Medicamentos , Qualidade de Vida/psicologia , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/epidemiologia , Discinesia Induzida por Medicamentos/psicologia , Discinesia Induzida por Medicamentos/terapia , Humanos , Incidência , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Fatores de RiscoRESUMO
L-DOPA-induced dyskinesias in Parkinson's disease are a significant clinical problem for which few therapies are available. We recently showed that nicotine reduces L-DOPA-induced abnormal involuntary movements (AIMs) in parkinsonian animals, suggesting it may be useful for the treatment of L-DOPA-induced dyskinesias. The present experiments were performed to understand the mechanisms whereby nicotine reduces L-DOPA-induced AIMs. We used a well established model of dyskinesias, L-DOPA-treated unilateral 6-hydroxydopamine-lesioned rats. Dose-ranging studies showed that injection of 0.1 mg/kg nicotine once or twice daily for 4 or 10 days most effectively reduced AIMs, with no worsening of parkinsonism. Importantly, a single nicotine injection did not reduce AIMs, indicating that nicotine's effect is caused by long-term rather than short-term molecular changes. Administration of the metabolite cotinine did not reduce AIMs, suggesting a direct effect of nicotine. Experiments with the nicotinic receptor (nAChR) antagonist mecamylamine were done to determine whether nicotine acted via a receptor-mediated mechanism. Unexpectedly, several days of mecamylamine injection (1.0 mg/kg) alone significantly ameliorated dyskinesias to a comparable extent as nicotine. The decline in AIMs with combined nicotine and mecamylamine treatment was not additive, suggesting that nicotine exerts its effects via a nAChR interaction. This latter finding, combined with data showing that mecamylamine reduced AIMs to a similar extent as nicotine, and that nicotine or mecamylamine treatment both decreased alpha6beta2* and increased alpha4beta2* nAChR expression, suggests that the nicotine-mediated improvement in L-DOPA-induced AIMs may involve a desensitization block. These data have important implications for the treatment of L-DOPA-induced dyskinesias in Parkinson's disease.
Assuntos
Antiparkinsonianos , Discinesia Induzida por Medicamentos/fisiopatologia , Levodopa , Receptores Nicotínicos/fisiologia , Anfetamina/farmacologia , Animais , Autorradiografia , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes , Bloqueadores dos Canais de Cálcio , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/análogos & derivados , Conotoxinas , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Lateralidade Funcional/efeitos dos fármacos , Masculino , Mecamilamina/farmacologia , Neostriado/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Piridinas , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacosRESUMO
This investigation was undertaken to study the effect of pentoxifylline (PTX) on iminodipropionitrile (IDPN)-induced behavioral abnormalities [excitation with choreiform and circling movements (ECC) syndrome] in rats. The animals were intraperitoneally injected with IDPN (100 mg/kg) daily for 7 days. PTX was administered daily 30 min before IDPN in the doses of 25, 50, and 100 mg/kg for 9 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex, and contact inhibition of the righting reflex. The onset of ECC syndrome was observed on day 8 in the group treated with IDPN alone; all animals in this group became dyskinetic on day 10. Co-treatment with PTX dose dependently delayed the onset time and significantly reduced the incidence and severity of IDPN-induced ECC syndrome; high dose of PTX completely inhibited the abnormal behavioral signs in IDPN-treated rats. Administration of IDPN caused significant depletions in cerebral glutathione and vitamin E levels. Treatment with PTX dose dependently attenuated IDPN-induced oxidative stress in rats. The beneficial effects of PTX against IDPN toxicity may be attributed to its antioxidant and anti-inflammatory properties.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Síndromes Neurotóxicas/tratamento farmacológico , Nitrilas/antagonistas & inibidores , Nitrilas/toxicidade , Pentoxifilina/farmacologia , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/psicologia , Glutationa/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/psicologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Vitamina E/metabolismoRESUMO
Long term use of typical neuroleptics such as haloperidol may be limited by unwanted motor side effects like tardive dyskinesia characterized by repetitive involuntary movements, involving the mouth, face and trunk. Atypical neuroleptics, such as clozapine and risperidone are devoid of these side effects. However the precise mechanisms of the neuronal toxicity induced by haloperidol are poorly understood. It is possible that typical and atypical antipsychotic differently affects neuronal survival and death and that these effects considerably contribute to the differences in the development of TD. The aim of the present study is to investigate the role of TNF-alpha and NFkappaB on the toxicity induced by chronic haloperidol administration in an animal model of tardive dyskinesia. Rats were treated for 21 days with: haloperidol (5 mg/kg), clozapine (5 and 10 mg/kg), risperidone (5 mg/kg) or saline. Orofacial dyskinetic movements and total locomotor activity was evaluated. Striatal levels of dopamine were measure by HPLC/ED whereas striatal levels of TNF-alpha and NFkappaB p65 subunit were measured by ELISA technique. Haloperidol increased orofacial dyskinetic movements and total locomotor activity (on day 22) (PAssuntos
Antipsicóticos/toxicidade
, Dopamina/metabolismo
, Discinesia Induzida por Medicamentos/metabolismo
, Transtornos dos Movimentos/metabolismo
, Neostriado/metabolismo
, Fator de Transcrição RelA/metabolismo
, Fator de Necrose Tumoral alfa/metabolismo
, Animais
, Comportamento Animal/efeitos dos fármacos
, Discinesia Induzida por Medicamentos/psicologia
, Haloperidol/toxicidade
, Masculino
, Atividade Motora/efeitos dos fármacos
, Transtornos dos Movimentos/psicologia
, Neostriado/efeitos dos fármacos
, Ratos
, Ratos Wistar
RESUMO
Levodopa is the most effective agent to alleviate motor dysfunction in Parkinson's disease but its long-term use is associated with the development of dyskinesias. Although the pathogenic processes behind the development of levodopa-induced dyskinesias are still being elucidated, it appears that chronic administration of this short-lived agent results in nonphysiologic pulsatile stimulation of striatal neurons and abnormal firing patterns in the basal ganglia. Dyskinesias have been associated with decreased quality of life, and a number of methodologies to evaluate severity of dyskinesias are now available. Strategies to avoid, reduce, or eliminate dyskinesias include providing more continuous dopaminergic stimulation, administering an antidyskinetic agent, and surgery. Several new compounds that may provide an antidyskinetic effect are also under investigation.
Assuntos
Antiparkinsonianos/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Levodopa/efeitos adversos , Idoso , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacologia , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/fisiopatologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Estimulação Encefálica Profunda , Dopamina/fisiologia , Agonistas de Dopamina/farmacologia , Esquema de Medicação , Discinesia Induzida por Medicamentos/fisiopatologia , Discinesia Induzida por Medicamentos/prevenção & controle , Discinesia Induzida por Medicamentos/psicologia , Discinesia Induzida por Medicamentos/terapia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Levodopa/administração & dosagem , Levodopa/farmacologia , Estudos Multicêntricos como Assunto , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Qualidade de Vida , Receptores de Glutamato/fisiologia , Índice de Gravidade de Doença , Ácido gama-Aminobutírico/fisiologiaRESUMO
Tardive dyskinesia (TD) is a motor disorder of the orofacial region resulting from chronic neuroleptic treatment. A high incidence and irreversibility of this hyperkinetic disorder has been considered a major clinical issue in the treatment of schizophrenia. The molecular mechanism related to the pathophysiology of tardive dyskinesia is not completely known. Various animal studies have demonstrated an enhanced oxidative stress and increased glutamatergic transmission as well as inhibition in the glutamate uptake after the chronic administration of haloperidol. The present study investigated the effect of curcumin, an antioxidant, in haloperidol-induced tardive dyskinesia by using different behavioural (orofacial dyskinetic movements, stereotypy, locomotor activity, % retention), biochemical (lipid peroxidation, reduced glutathione levels, antioxidant enzyme levels (SOD and catalase) and neurochemical (neurotransmitter levels) parameters. Chronic administration of haloperidol (1 mg/kg i.p. for 21 days) significantly increased vacuous chewing movements (VCM's), tongue protrusions, facial jerking in rats which was dose-dependently inhibited by curcumin. Chronic administration of haloperidol also resulted in increased dopamine receptor sensitivity as evident by increased locomotor activity and stereotypy and also decreased % retention time on elevated plus maze paradigm. Pretreatment with curcumin reversed these behavioral changes. Besides, haloperidol also induced oxidative damage in all major regions of brain which was attenuated by curcumin, especially in the subcortical region containing striatum. On chronic administration of haloperidol, there was a decrease in turnover of dopamine, serotonin and norepinephrine in both cortical and subcortical regions which was again dose-dependently reversed by treatment with curcumin. The findings of the present study suggested for the involvement of free radicals in the development of neuroleptic-induced tardive dyskinesia and point to curcumin as a possible therapeutic option to treat this hyperkinetic movement disorder.
Assuntos
Antidiscinéticos , Antipsicóticos/antagonistas & inibidores , Antipsicóticos/toxicidade , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Curcuma/química , Curcumina/uso terapêutico , Discinesia Induzida por Medicamentos/prevenção & controle , Haloperidol/antagonistas & inibidores , Haloperidol/toxicidade , Animais , Ansiolíticos/farmacologia , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Neurotransmissores/metabolismo , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Several neurological diseases are related to oxidative stress (OS) and neurotoxicity. Considering that physical exercise may exert beneficial effects on antioxidant defenses, our objective was to evaluate the influence of a swimming exercise on an OS animal model (reserpine-induced orofacial dyskinesia). In this model, the increased dopamine metabolism can generate OS and neuronal degeneration, causing involuntary movements. The increase in vacuous chewing movements and facial twitching caused by reserpine (1 mg/kg s.c.) was partially prevented by exercise. An increase in catalase activity and a decrease in GSH levels were observed in the striatum. Physical training did not change the effects of reserpine on catalase, however it partially recovered GSH. Exercise per se caused a significant GSH decrease. There was a positive correlation between catalase and OD (r=0.41; r=0.47, P<0.05) and a negative correlation between GSH and OD (r=0.61; r=0.71, P<0.05). These results reveal the benefit of exercise in attenuating the motor disorder related to OS.
Assuntos
Antioxidantes/metabolismo , Antipsicóticos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Reserpina/farmacologia , Animais , Antipsicóticos/toxicidade , Química Encefálica/efeitos dos fármacos , Catalase/sangue , Discinesia Induzida por Medicamentos/psicologia , Glutationa/sangue , Masculino , Ratos , Ratos Wistar , Análise de Regressão , Reserpina/toxicidadeRESUMO
Levodopa-induced dyskinesias (LID) are common and difficult to treat. This review focuses on three issues related to LID: clinical features, classification and rating, pathophysiology and pathogenesis, and management. The three primary clinical syndromes are OFF-period dystonia, peak-dose dyskinesia, and diphasic dyskinesia. Several other forms also occur, making the evaluation and choice of treatment complicated. A core component of the pathophysiology of LID is overactivity of the direct striatal output pathway. This pathway provides a direct GABAergic connection by which the striatum inhibits the output regions of the basal ganglia, i.e., the internal globus pallidus and the substantia nigra pars reticulata. Altering dopaminergic dosing and timing can abate dyskinesias, but usually impact the control of parkinsonism. Putative therapies to reduce the problem of dyskinesias could focus on the glutamatergic, GABAergic, alpha2 adrenergic, serotonergic (5HT1A, 5HT2A), opioid, histamine H3, adenosine A2A receptors, the monoamine transport or cannabinoid CB1 receptors systems. The only currently available drug with an evidence-based recommendation on efficacy for dyskinesia is amantadine. Therapy goals include the prevention of dyskinesia and treatment of dyskinesias that are troublesome clinically. New rating measures to assess severity and disability related to dyskinesia are in the process of development and clinimetric testing.
Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Levodopa/efeitos adversos , Discinesia Induzida por Medicamentos/epidemiologia , Discinesia Induzida por Medicamentos/psicologia , Discinesia Induzida por Medicamentos/terapia , Humanos , Doença de Parkinson/tratamento farmacológico , PubMed/estatística & dados numéricos , Qualidade de Vida , Literatura de Revisão como AssuntoRESUMO
The purpose of this paper is to report Health Utility Index Mark 3 (HUI3) scores, at baseline and at one year, for patients with psychotic disorders. Eighty two randomly selected outpatients from a Montreal teaching hospital completed the HUI3 and other measures of symptoms and side-effects. At baseline, the average Global Utility score was 0.64, which is rated in the "dysfunctional" health status range. Improvements were seen at one year follow-up in the Global, Dexterity, Cognition, and Pain Utility scores. The proportion of individuals rated in the "healthy" health status range improved by 32% from baseline to one year. HUI3 scores were negatively related to measures of psychotic symptoms and side-effects. We propose that the HUI3 should be used to assess health-related quality of life (HRQOL) in patients with psychotic disorders. Scores could be compared with other populations affected with chronic conditions (e.g., Alzheimer dementia, cancer, arthritis, etc.).
Assuntos
Indicadores Básicos de Saúde , Transtornos Psicóticos/psicologia , Qualidade de Vida/psicologia , Esquizofrenia/diagnóstico , Psicologia do Esquizofrênico , Perfil de Impacto da Doença , Adulto , Assistência Ambulatorial , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Continuidade da Assistência ao Paciente , Discinesia Induzida por Medicamentos/diagnóstico , Discinesia Induzida por Medicamentos/psicologia , Feminino , Hospitais de Ensino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/tratamento farmacológico , Quebeque , Esquizofrenia/tratamento farmacológicoRESUMO
"Dopamine stabilizers" are a new class of compounds that have the ability to reverse both hypo- as well as hyperdopaminergia in vivo. This class, exemplified by the phenylpiperidines (S)-(-)-3-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonyl-phenyl)-1-propyl)-piperidine [ACR16] although lacking high in vitro binding affinity for dopamine D2 receptor [(-)-OSU6162, Ki = 447 nM; ACR16, Ki > 1 microM], shows functional actions, suggestive of their interaction. Hence, we evaluated in vivo D2 occupancy of these agents in rats and correlated it to observed effects in a series of behavioral, neurochemical, and endocrine models relevant to the dopamine system and antipsychotic effect. Both (-)-OSU6162 and ACR16 showed robust dose-dependent striatal D2 occupancy with ED50 values of 5.27 and 18.99 mg/kg s.c., respectively, and functional assays showed no partial agonism. Over an occupancy range of 37 to 87% (3-60 mg/kg) for (-)-OSU6162 and 35 to 74% (10-60 mg/kg) for ACR16, we observed both inhibitory (amphetamine-induced locomotor activity) and stimulatory effects (in habituated rats). Haloperidol, over a similar occupancy range (33-78%), potently inhibited psychostimulant activity and induced catalepsy, but it failed to activate habituated animals. In the conditioned avoidance response assay, ACR16 was clearly more efficacious than (-)-OSU6162. In addition, both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens compared with the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychotic-like effects, with low motor side effect liability, in a dose range that corresponds to high D2 in vivo occupancy.
Assuntos
Antipsicóticos , Dopaminérgicos/farmacologia , Discinesia Induzida por Medicamentos/psicologia , Piperidinas/farmacologia , Receptores de Dopamina D2/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Di-Hidroxifenilalanina/metabolismo , Dopaminérgicos/metabolismo , Dopaminérgicos/toxicidade , Antagonistas de Dopamina/metabolismo , Haloperidol/metabolismo , Imuno-Histoquímica , Masculino , Atividade Motora/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Piperidinas/metabolismo , Piperidinas/toxicidade , Prolactina/sangue , Proteínas Proto-Oncogênicas c-fos/biossíntese , Ratos , Ratos Sprague-Dawley , Reserpina/metabolismoRESUMO
To study behavioral character and changes of neuronal activity in the basal ganglia of rat model of levodopa-induced dyskinesia, unilateral 6-hydroxydopamine lesioned rat model of Parkinson disease (PD) was treated with levodopa/benserazide twice daily for 4 weeks and the behavior observed on the 1st, 3rd, 4th, 7th, 9th, 10th, 14th, 21st and 28th day. The animals were sacrificed and immunohistochemical technique was used to measure the changes of Fos expression in the caudate putamen (CPU), globus pallidus (GP) and sensorimotor area of cerebral cortex 2 h after the last treatment. The results showed that pulsatile treatment with a subthreshold dose of levodopa gradually induced abnormal involuntary movement (AIM), including stereotypy (limb dyskinesia, axial dystonia and masticatory dyskinesia) towards the side contralateral to the dopamine-denervated striatum and increased contraversive rotation. The motor pattern of each subtype was highly stereotypic across individual rats, and the proportion of each subtype was not consistent among individual rats. Fos positive nuclei in the CPU and GP were increased by levodopa acute administration, and more remarkably in the CPU, but not in the cerebral cortex. After repeated levodopa treatment. Fos positive nuclei were reduced remarkably in the CPU, but were increased in the GP and cerebral cortex. It was concluded that the neural mechanisms underlying levodopa induced AIM in rat model of PD was very similar to those seen in levodopa-induced dyskinesia (LID) in PD patients and MPTP-lesioned monkeys, and increased striatopallidal neuronal activity might be involved in occurrence of LID.
Assuntos
Antiparkinsonianos/toxicidade , Gânglios da Base/metabolismo , Discinesia Induzida por Medicamentos/psicologia , Levodopa/toxicidade , Doença de Parkinson/psicologia , Proteínas Proto-Oncogênicas c-fos/biossíntese , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/etiologia , Masculino , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
Iminodipropionitrile (IDPN) produces irreversible behavioral abnormalities characterized by excitation with choreiform and circling movements (ECC) syndrome in rodents. Concomitant exposure to drugs or environmental chemicals has been shown to alter IDPN-induced neurobehavioral toxicity. This investigation was undertaken to study the effect of sodium salicylate (SS) on IDPN-induced behavioral abnormalities in rats. The animals were exposed to IDPN (100 mg/kg ip) daily for 8 days. SS was administered daily 30 min before IDPN in the doses of 50, 100 and 200 mg/kg ip for 12 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex and contact inhibition of the righting reflex. Horizontal and vertical locomotor activities and forelimbs grip strength were also measured. After behavioral studies, the animals were sacrificed, and the cerebrum and temporal bones were collected for glutathione analysis and inner ear histopathology, respectively. The onset of ECC syndrome was observed on Day 9 in the IDPN-alone group with 100% incidence on Day 12. Cotreatment with salicylate dose-dependently delayed the onset time and significantly attenuated the incidence and severity of IDPN-induced neurobehavioral signs. IDPN alone significantly increased horizontal motor activity and reduced vertical motor activity and forelimbs grip strength; these effect were significantly reversed by salicylate treatment. Treatment with salicylate also attenuated IDPN-induced depletion of GSH in the cerebrum, suggesting its free radical scavenging property.
Assuntos
Comportamento Animal/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/psicologia , Nitrilas/antagonistas & inibidores , Nitrilas/toxicidade , Salicilato de Sódio/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/psicologia , Orelha Interna/efeitos dos fármacos , Orelha Interna/patologia , Feminino , Glutationa/metabolismo , Força da Mão/fisiologia , Atividade Motora/efeitos dos fármacos , Síndromes Neurotóxicas/patologia , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: This study was undertaken to evaluate whether peripheral (serum) markers of iron status are associated with severity of the choreoathetoid movements seen in tardive dyskinesia (TD). METHODS: Serum iron indices (ferritin, iron, and total iron binding capacity) and fluphenazine levels were measured in a group of 30 male DSM-III diagnosed schizophrenic patients chronically treated with fluphenazine decanoate. The severity of choreoathetoid movements was assessed with the Abnormal Involuntary Movement Scale (AIMS), and akathisia was assessed with the Barnes scale. RESULTS: A significant positive correlation was observed between AIMS scores and serum ferritin. This relationship remained significant after controlling for age and plasma fluphenazine levels. No significant correlations were observed between serum iron or total iron binding capacity and choreoathetoid movement ratings. There were no significant associations between serum iron indices and akathisia ratings. CONCLUSIONS: The data suggest that choreoathetoid movements are associated with serum ferritin levels in chronically medicated male schizophrenic patients. This relationship does not seem to be caused by an association of these variable with age or plasma fluphenazine levels. In addition, the relationship seems to be specific, since other iron indices and another extrapyramidal side effect (akathisia) do not demonstrate a similar relationship. In view of reports that antipsychotic medications change normal iron metabolism and increase iron uptake into the brain, the current results could be interpreted to suggest that serum ferritin levels may be a risk factor for TD in patients treated with "classic" antipsychotic medications.