RESUMO
Parkinson's Disease (PD) is a neurodegenerative movement disorder characterized by dopamine (DA) cell loss in the substantia nigra pars compacta (SNc). As PD progresses, patients display disruptions in gait such as changes in posture, bradykinesia, and shortened stride. DA replacement via L-DOPA alleviates many PD symptoms, though its effects on gait are not well demonstrated. This study aimed to assess the relationship between DA lesion, gait, and deficit-induced reversal with L-DOPA. To do so, Sprague-Dawley rats (N = 25, 14 males, 11 females) received unilateral medial forebrain bundle (MFB) DA lesions with 6-hydroxydopamine (6-OHDA). An automated gait analysis system assessed spatiotemporal gait parameters pre- and post-lesion, and after various doses of L-DOPA (0, 3, or 6 mg/kg; s.c.). The forepaw adjusting steps (FAS) test was implemented to evaluate lesion efficacy while the abnormal involuntary movements (AIMs) scale monitored the emergence of L-DOPA-induced dyskinesia (LID). High performance liquid chromatography (HPLC) assessed changes in brain monoamines on account of lesion and treatment. Results revealed lesion-induced impairments in gait, inclusive of max-contact area and step-sequence alterations that were not reversible with L-DOPA. However, the emergence of AIMs were observed at higher doses. Post-mortem, 6-OHDA lesions induced a loss of striatal DA and norepinephrine (NE), while prefrontal cortex (PFC) displayed noticeable reduction in NE but not DA. Our findings indicate that hemiparkinsonian rats display measurable gait disturbances similar to PD patients that are not rescued by DA replacement. Furthermore, non-DA mechanisms such as attention-related NE in PFC may contribute to altered gait and may constitute a novel target for its treatment.
Assuntos
Transtornos Neurológicos da Marcha , Levodopa , Oxidopamina , Ratos Sprague-Dawley , Animais , Levodopa/farmacologia , Levodopa/efeitos adversos , Masculino , Feminino , Ratos , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Antiparkinsonianos/farmacologia , Modelos Animais de Doenças , Feixe Prosencefálico Mediano/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/patologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Lateralidade Funcional/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Marcha/efeitos dos fármacos , Discinesia Induzida por MedicamentosRESUMO
A functional lateralization has been reported in control of emotional responses by the medial prefrontal cortex (mPFC). However, a hemisphere asymmetry in involvement of the mPFC in expression of fear conditioning responses has never been reported. Therefore, we investigated whether control by mPFC of freezing and cardiovascular responses during re-exposure to an aversively conditioned context is lateralized. For this, rats had guide cannulas directed to the mPFC implanted bilaterally or unilaterally in the right or left hemispheres. Vehicle or the non-selective synaptic inhibitor CoCl2 was microinjected into the mPFC 10 min before re-exposure to a chamber where the animals had previously received footshocks. A catheter was implanted into the femoral artery before the fear retrieval test for cardiovascular recordings. We observed that bilateral microinjection of CoCl2 into the mPFC reduced both the freezing behavior (enhancing locomotion and rearing) and arterial pressure and heart rate increases during re-exposure to the aversively conditioned context. Unilateral microinjection of CoCl2 into the right hemisphere of the mPFC also decreased the freezing behavior (enhancing locomotion and rearing), but without affecting the cardiovascular changes. Conversely, unilateral synaptic inhibition in the left mPFC did not affect either behavioral or cardiovascular responses during fear retrieval test. Taken together, these results suggest that the right hemisphere of the mPFC is necessary and sufficient for expression of freezing behavior to contextual fear conditioning. However, the control of cardiovascular responses and freezing behavior during fear retrieval test is somehow dissociated in the mPFC, being the former bilaterally processed.
Assuntos
Cobalto , Medo , Lateralidade Funcional , Córtex Pré-Frontal , Animais , Córtex Pré-Frontal/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Masculino , Cobalto/farmacologia , Medo/fisiologia , Medo/efeitos dos fármacos , Ratos , Lateralidade Funcional/fisiologia , Lateralidade Funcional/efeitos dos fármacos , Emoções/fisiologia , Emoções/efeitos dos fármacos , Ratos Wistar , Frequência Cardíaca/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Microinjeções , Condicionamento Clássico/fisiologia , Condicionamento Clássico/efeitos dos fármacosRESUMO
RATIONALE: Chronic stress exposure disrupts the medial prefrontal cortex's (mPFC) ability to regulate impulses, leading to the loss of control over alcohol drinking in rodents, emphasizing the critical role of this forebrain area in regulating alcohol consumption. Moreover, chronic stress exposure causes lateralization of mPFC functions with volumetric and functional changes, resulting in hyperactivity in the right hemisphere and functional decrease in the left. OBJECTIVES: This study investigated the inhibitory role of the left prelimbic cortex (LPrL) on ethanol consumption induced by chronic social defeat stress (SDS) in male mice and to examine if inactivation of the LPrL causes disinhibition of the right mPFC, leading to an increase in ethanol consumption. We also investigated the role of lateralization and neurochemical alterations in the mPFC related to ethanol consumption induced by chronic SDS. To this end, we examined the activation patterns of ΔFosB, VGLUT2, and GAD67 in the left and right mPFC. RESULTS: Temporarily blocking the LPrL or right PrL (RPrL) cortices during acute SDS did not affect male mice's voluntary ethanol consumption in male mice. When each cortex was blocked in mice previously exposed to chronic SDS, ethanol consumption also remained unaffected. However, male mice with LPrL lesions during chronic SDS showed an increase in voluntary ethanol consumption, which was associated with enhanced ΔFosB/VGLUT2-positive neurons within the RPrL cortex. CONCLUSIONS: The results suggest that the LPrL may play a role in inhibiting ethanol consumption induced by chronic SDS, while the RPrL may be involved in the disinhibition of ethanol consumption.
Assuntos
Consumo de Bebidas Alcoólicas , Córtex Pré-Frontal , Derrota Social , Estresse Psicológico , Animais , Masculino , Estresse Psicológico/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Camundongos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Etanol/administração & dosagem , Etanol/farmacologia , Lateralidade Funcional/efeitos dos fármacos , Doença CrônicaRESUMO
Motor disturbances are observed in schizophrenia patients, but the neuroanatomical background is unknown. Our aim was to investigate the pyramidal cells of the primary motor cortex (BA 4) in both hemispheres of postmortem control and schizophrenia subjects-8 subjects in each group-with 2.5-5.5 h postmortem interval. The density and size of the Sternberger monoclonal incorporated antibody 32 (SMI32)-immunostained pyramidal cells in layer 3 and 5 showed no change; however, the proportion of larger pyramidal cells is decreased in layer 5. Giant pyramidal neurons (Betz cells) were investigated distinctively with SMI32- and parvalbumin (PV) immunostainings. In the right hemisphere of schizophrenia subjects, the density of Betz cells was decreased and their PV-immunopositive perisomatic input showed impairment. Part of the Betz cells contained PV in both groups, but the proportion of PV-positive cells has declined with age. The rat model of antipsychotic treatment with haloperidol and olanzapine showed no differences in size and density of SMI32-immunopositive pyramidal cells. Our results suggest that motor impairment of schizophrenia patients may have a morphological basis involving the Betz cells in the right hemisphere. These alterations can have neurodevelopmental and neurodegenerative explanations, but antipsychotic treatment does not explain them.
Assuntos
Lateralidade Funcional , Córtex Motor , Células Piramidais , Esquizofrenia , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Envelhecimento , Antipsicóticos/uso terapêutico , Autopsia , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Lateralidade Funcional/efeitos dos fármacos , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Imuno-Histoquímica , Filamentos Intermediários/metabolismo , Córtex Motor/efeitos dos fármacos , Córtex Motor/patologia , Olanzapina/farmacologia , Olanzapina/uso terapêutico , Parvalbuminas/metabolismo , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , Ratos Sprague-Dawley , Análise de Regressão , Esquizofrenia/tratamento farmacológico , Esquizofrenia/patologiaRESUMO
Ischemic stroke is a major cause of morbidity and mortality worldwide and only few affected patients are able to receive treatment, especially in developing countries. Detailed pathophysiology of brain ischemia has been extensively studied in order to discover new treatments with a broad therapeutic window and that are accessible to patients worldwide. The nucleoside guanosine (Guo) has been shown to have neuroprotective effects in animal models of brain diseases, including ischemic stroke. In a rat model of focal permanent ischemia, systemic administration of Guo was effective only when administered immediately after stroke induction. In contrast, intranasal administration of Guo (In-Guo) was effective even when the first administration was 3 h after stroke induction. In order to validate the neuroprotective effect in this larger time window and to investigate In-Guo neuroprotection under global brain dysfunction induced by ischemia, we used the model of thermocoagulation of pial vessels in Wistar rats. In our study, we have found that In-Guo administered 3 h after stroke was capable of preventing ischemia-induced dysfunction, such as bilateral suppression and synchronicity of brain oscillations and ipsilateral cell death signaling, and increased permeability of the blood-brain barrier. In addition, In-Guo had a long-lasting effect on preventing ischemia-induced motor impairment. Our data reinforce In-Guo administration as a potential new treatment for brain ischemia with a more suitable therapeutic window.
Assuntos
Encéfalo/fisiopatologia , Guanosina/administração & dosagem , Guanosina/uso terapêutico , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/fisiopatologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Administração Intranasal , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Veias Cerebrais/efeitos dos fármacos , Eletrocoagulação , Eletroencefalografia/efeitos dos fármacos , Lateralidade Funcional/efeitos dos fármacos , AVC Isquêmico/complicações , Masculino , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/prevenção & controle , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
The endogenous neurotransmitter acetylcholine (ACh) is known to affect the excitatory/inhibitory (E/I) balance of primate visual cortex, enhancing feedforward thalamocortical gain while suppressing corticocortical synapses. Recent advances in the study of the human visual system suggest that ACh is a likely component underlying interocular interactions. However, our understanding of its precise role in binocular processes is currently lacking. Here we use binocular rivalry as a probe of interocular dynamics to determine ACh's effects, via the acetylcholinesterase inhibitor (AChEI) donepezil, on the binocular visual system. A total of 23 subjects (13 male) completed two crossover experimental sessions where binocular rivalry measurements were obtained before and after taking either donepezil (5 mg) or a placebo (lactose) pill. We report that enhanced cholinergic potentiation attenuates perceptual suppression during binocular rivalry, reducing the overall rate of interocular competition while enhancing the visibility of superimposition mixed percepts. Considering recent evidence that perceptual suppression during binocular rivalry is causally modulated by the inhibitory neurotransmitter GABA, our results suggest that cholinergic activity counteracts the effect of GABA with regards to interocular dynamics and may modulate the inhibitory drive within the visual cortex.SIGNIFICANCE STATEMENT Our research demonstrates that the cholinergic system is implicated in modulating binocular interactions in the human visual cortex. Potentiating the transmission of acetylcholine (ACh) via the cholinergic drug donepezil reduces the extent to which the eyes compete for perceptual dominance when presented two separate, incongruent images.
Assuntos
Sistema Nervoso Parassimpático/fisiologia , Visão Binocular/fisiologia , Acetilcolina/farmacologia , Adulto , Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologia , Estudos Cross-Over , Donepezila/farmacologia , Feminino , Lateralidade Funcional/efeitos dos fármacos , Humanos , Masculino , Sistema Nervoso Parassimpático/efeitos dos fármacos , Estimulação Luminosa , Desempenho Psicomotor/efeitos dos fármacos , Disparidade Visual , Visão Binocular/efeitos dos fármacos , Adulto Jovem , Ácido gama-Aminobutírico/fisiologiaRESUMO
PURPOSE: This study aimed to describe and analyze psychomotor functions in patients with drug-resistant epilepsy and identify factors associated with psychomotor deficits. METHODS: We performed a prospective case-control study comparing psychomotor skill performances in 40 adult patients and 80 healthy individuals between October 2017 and March 2018. Psychomotor functions were examined in both patients and controls using a full set of specific tests (Rey-Osterrieth complex figure test, Zazzo's cancelation task, Piaget-Head test, and paired images test). Potential risk factors for psychomotor deficit were assessed in the patient group using a multivariate analysis. RESULTS: The two groups did not differ in age, sex, dominant hand, and level of education. Compared with the control group, patients with drug-resistant epilepsy showed worse performance on global psychomotor functions and, more selectively, in assessments exploring perceptual organization and visuospatial memory, laterality awareness, sustained attention, concentration, visual scanning, inhibition, and impulsivity. In the patient group, psychomotor deficits were associated with the severity of epilepsy (epileptic encephalopathy, high seizure frequency, heavy antiepileptic medication). CONCLUSION: Psychomotor deficits could therefore be systematically detected in patients with drug-resistant epilepsy in order to provide psychomotor therapy and improve quality of life.
Assuntos
Epilepsia Resistente a Medicamentos/psicologia , Testes Neuropsicológicos , Estimulação Luminosa/métodos , Desempenho Psicomotor/fisiologia , Adolescente , Adulto , Atenção/fisiologia , Estudos de Casos e Controles , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/cirurgia , Feminino , Lateralidade Funcional/efeitos dos fármacos , Lateralidade Funcional/fisiologia , Humanos , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
The influence of testosterone on the development of human brain lateralization has been subject of debate for a long time, partly because studies investigating this are necessarily mostly correlational. In the present study we used a quasi-experimental approach by assessing functional brain lateralization in trans boys (female sex assigned at birth, diagnosed with Gender Dysphoria, n = 21) before and after testosterone treatment, and compared these results to the functional lateralization of age-matched control groups of cisgender boys (n = 20) and girls (n = 21) around 16 years of age. The lateralization index of the amygdala was determined with functional magnetic resonance imaging (fMRI) during an emotional face matching task with angry and fearful faces, as the literature indicates that boys show more activation in the right amygdala than girls during the perception of emotional faces. As expected, the lateralization index in trans boys shifted towards the right amygdala after testosterone treatment, and the cumulative dose of testosterone treatment correlated significantly with amygdala lateralization after treatment. However, we did not find any significant group differences in lateralization and endogenous testosterone concentrations predicted rightward amygdala lateralization only in the cis boys, but not in cis girls or trans boys. These inconsistencies may be due to sex differences in sensitivity to testosterone or its metabolites, which would be a worthwhile course for future studies.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Testosterona/farmacologia , Pessoas Transgênero/psicologia , Adolescente , Tonsila do Cerebelo/metabolismo , Encéfalo/metabolismo , Emoções/fisiologia , Expressão Facial , Feminino , Lateralidade Funcional/efeitos dos fármacos , Disforia de Gênero/fisiopatologia , Identidade de Gênero , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Homens , Caracteres Sexuais , Testosterona/metabolismo , Transexualidade/tratamento farmacológico , Transexualidade/metabolismo , MulheresRESUMO
INTRODUCTION: Frontal alpha asymmetry (FAA) is a proposed prognostic biomarker in major depressive disorder (MDD), conventionally acquired with electroencephalography (EEG). Although small studies attributed trait-like properties to FAA, a larger sample is needed to reliably asses this characteristic. Furthermore, to use FAA to predict treatment response, determining its stability, including the potential dependency on depressive state or medication, is essential. METHODS: In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, randomized, prospective open-label trial, 1008 MDD participants were randomized to treatment with escitalopram, sertraline or venlafaxine-extended release. Treatment response was established eight weeks after treatment initiation and resting state EEG was measured both at baseline and after eight weeks (nâ¯=â¯453). RESULTS: FAA did not change significantly after eight weeks of treatment (nâ¯=â¯453, pâ¯=â¯.234), nor did we find associations with age, sex, depression severity, or change in depression severity. After randomizing females to escitalopram or sertraline, for whom treatment response could be predicted in an earlier study, FAA after eight weeks resulted in equivalent response prediction as baseline FAA (one tailed pâ¯=â¯.028). CONCLUSION: We demonstrate that FAA is a stable trait, robust to time, state and pharmacological status. This confirms FAA stability. Furthermore, as prediction of treatment response is irrespective of moment of measurement and use of medication, FAA can be used as a state-invariant prognostic biomarker with promise to optimize MDD treatments.
Assuntos
Ritmo alfa/fisiologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/fisiopatologia , Lobo Frontal/fisiopatologia , Lateralidade Funcional/fisiologia , Adulto , Ritmo alfa/efeitos dos fármacos , Antidepressivos/administração & dosagem , Biomarcadores , Citalopram/administração & dosagem , Citalopram/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Eletroencefalografia , Feminino , Lobo Frontal/efeitos dos fármacos , Lateralidade Funcional/efeitos dos fármacos , Humanos , Masculino , Estudos Prospectivos , Sertralina/administração & dosagem , Sertralina/uso terapêutico , Resultado do Tratamento , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/uso terapêuticoRESUMO
The involvement of fronto-striatal circuits in item and associative memory retrieval as well as in the stabilization of memories by retrieval practice suggests that both retrieval and re-encoding of stored memories might rely on dopaminergic mechanisms in humans. We tested these hypotheses in a placebo-controlled pharmacological fMRI study using 2 mg of the D2 antagonist haloperidol administered acutely before a cued associative recall task of previously encoded picture-word pairs in 53 healthy humans of both sexes. The cued associative recall was moreover repeated 3 d later outside the scanner without pharmacological intervention. Dopaminergic modulation significantly improved associative recall performance and recognition accuracy of verbal items. Moreover, we observed a significant dopamine effect on re-encoding in terms of increased specificity of associative memories from the first to the second cued associative recall. Better association memory under haloperidol was linked with higher activity in the left lateral prefrontal cortex and right parietal cortex, suggesting that dopamine facilitates associative retrieval through increased recruitment of frontoparietal monitoring processes. In contrast, improved recognition of verbal items under haloperidol was reflected by enhanced novelty detection in the hippocampus and increased activity in saliency networks. Together, these results show distinct but concomitant positive effects of dopamine on associative recall and item recognition and suggest that the specificity of associative recall through re-encoding mechanisms is likewise augmented by dopamine.SIGNIFICANCE STATEMENT Although the neurotransmitter dopamine has been linked with learning and memory for a long time, dopaminergic effects on item recognition in humans were demonstrated only recently. The involvement of fronto-striatal monitoring processes in association retrieval suggests that associative memory might be particularly affected by dopamine. Moreover, fronto-striatal dopaminergic signals have been hypothesized to determine the updating and re-encoding of previously retrieved memories. We here demonstrate clear facilitative effects of dopamine on associative recall and item recognition mediated by prefrontal and hippocampal mechanisms respectively. Additionally, effects on re-encoding were reflected by increased specificity of associative memories. These results augment our understanding of dopaminergic processes in episodic memory retrieval and offer new perspectives on memory impairments in dopamine-related disorders and their treatment.
Assuntos
Associação , Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Percepção/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Adulto , Sinais (Psicologia) , Antagonistas de Dopamina/farmacologia , Método Duplo-Cego , Feminino , Lateralidade Funcional/efeitos dos fármacos , Haloperidol/farmacologia , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/efeitos dos fármacos , Córtex Pré-Frontal/diagnóstico por imagem , Desempenho Psicomotor/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Adulto JovemRESUMO
PURPOSE: To review our experience with the Etomidate speech test (EST) for lateralizing language in children undergoing epilepsy surgery evaluation METHODS: This retrospective study included children (<18 years) with drug refractory focal epilepsy undergoing EST for bilateral or poorly reliable language representation on functional MRI. Data for consecutive children who underwent EST between January 2013 to June 2017 were reviewed. RESULTS: Twenty-one children (mean age at EST, 13.1⯱â¯4.4 years) were studied, with 19-right hemispheric and 20 left hemispheric injections. Six patients had neurological co-morbidities. Duration of ipsilateral EEG slowing was sufficient for speech testing in all children with a single bolus of Etomidate per carotid artery. Language was lateralized to one hemisphere in 17 (80.9%) and bilateral in two cases. EST was unsuccessful in two patients because of diffuse EEG slowing. Contralateral transient frontal EEG slowing was seen in 14 (73.7%) cases. EST was well tolerated in all the patients. CONCLUSIONS: The EST was found to be successful and safe in lateralizing language in most of our drug refractory pediatric epilepsy cohort.
Assuntos
Epilepsia/fisiopatologia , Etomidato/farmacologia , Memória/efeitos dos fármacos , Fala/efeitos dos fármacos , Adolescente , Adulto , Amobarbital , Criança , Epilepsia/tratamento farmacológico , Etomidato/efeitos adversos , Feminino , Lateralidade Funcional/efeitos dos fármacos , Lateralidade Funcional/fisiologia , Humanos , Idioma , Masculino , Memória/fisiologia , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: Central poststroke pain (CPSP) is the neuropathic pain in areas of the body corresponding to stroke lesions. It is often refractory to treatment, reduces quality of life, and impedes rehabilitation. The pharmacological treatment of CPSP is challenging. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is known to be effective against neuropathic pain. The current study describes the efficacy of duloxetine in reducing pain severity in CPSP patients. SUBJECTS AND METHODS: For the purpose of this study, CPSP was defined as spontaneous pain within an area of the body corresponding to the brain lesion that emerged at or after stroke onset. Any previously prescribed medical therapy for the patients was not changed or stopped; duloxetine 30 mg was added to their ongoing treatment. Pain was assessed at baseline and thereafter at 1 and 3 weeks using Numeric Rating Scale (NRS) and Short-form MC Gill Pain Questionnaire scores. At the first follow-up, scores were reviewed and dose was doubled if no improvement or adverse effects were observed. RESULTS: From a total of 37 patients, 4 were withdrawn because of adverse effects including nausea, agitation, and somnolence. The mean elapsed time of observed symptoms since stroke onset was 3.1 ± 4.1 years. There was a significant difference between the mean values of Short-form MC Gill Pain Questionnaire and NRS scores at baseline and those at the follow-up assessment. Twenty-six (70.3%) of the patients showed at least 30% reduction of NRS compared with baseline at the third week. CONCLUSIONS: Our findings suggest that duloxetine can be effective for managing CPSP.
Assuntos
Analgésicos/uso terapêutico , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Cloridrato de Duloxetina/uso terapêutico , Acidente Vascular Cerebral/complicações , Idoso , Dor Crônica/diagnóstico por imagem , Feminino , Seguimentos , Lateralidade Funcional/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Allopregnanolone is a neurosteroid implicated in mood disorders such as depression and anxiety. It acts as a GABAA receptor (GABAAR)-positive allosteric modulator and changes the expression of GABAAR subunits and of brain-derived neurotrophic factor (BDNF) in different brain regions. It has been demonstrated that such neurochemical changes may have an asymmetrical pattern regarding brain hemispheres. The aim of this study was to verify the behavioral and hemisphere-specific neurochemical effects of the bilateral intra-prefrontal cortex (intra-PFC) infusion of allopregnanolone in rats. Rats were exposed to the forced swim test and to the grooming microstructure test, followed by the right and left hemisphere-specific quantification of mRNA expression by Real-Time PCR of δ and γ2 GABAAR subunits and BDNF in the PFC and in the hippocampus. Though we did not observe any significant effects in the behavioral tests, intra-PFC allopregnanolone infusion bilaterally increased the mRNA expression of the δ subunit in the same area and of BDNF in the hippocampus. Both mRNA expressions of the γ2 subunit and BDNF were higher in the right than in the left PFC of control animals, and the hemisphere differences were not seen after allopregnanolone infusion. Overall hippocampal BDNF expression was also higher in the right hemisphere, but this asymmetry was not normalized by allopregnanolone. No asymmetries or changes were observed in the hippocampal mRNA expression of GABAAR subunits. These results point to a hemisphere-dependent regulation of GABAAR subunits and BDNF that can be modulated by intra-PFC allopregnanolone infusion, even in the absence of associated behavioral effects.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lateralidade Funcional/efeitos dos fármacos , GABAérgicos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Pregnanolona/farmacologia , Receptores de GABA-A/metabolismo , Animais , Depressão/tratamento farmacológico , Depressão/metabolismo , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Psicotrópicos/farmacologia , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos WistarRESUMO
Traumatic brain injury (TBI) results in well-known, significant alterations in structural and functional connectivity. Although this is especially likely to occur in areas of pathology, deficits in function to and from remotely connected brain areas, or diaschisis, also occur as a consequence to local deficits. As a result, consideration of the network wiring of the brain may be required to design the most efficacious rehabilitation therapy to target specific functional networks to improve outcome. In this work, we model remote connections after controlled cortical impact injury (CCI) in the rat through the effect of callosal deafferentation to the opposite, contralesional cortex. We show rescue of significantly reaching deficits in injury-affected forelimb function if temporary, neuromodulatory silencing of contralesional cortex function is conducted at 1 week post-injury using the γ-aminobutyric acid (GABA) agonist muscimol, compared with vehicle. This indicates that subacute, injury-induced remote circuit modifications are likely to prevent normal ipsilesional control over limb function. However, by conducting temporary contralesional cortex silencing in the same injured rats at 4 weeks post-injury, injury-affected limb function either remains unaffected and deficient or is worsened, indicating that circuit modifications are more permanently controlled or at least influenced by the contralesional cortex at extended post-injury times. We provide functional magnetic resonance imaging (MRI) evidence of the neuromodulatory effect of muscimol on forelimb-evoked function in the cortex. We discuss these findings in light of known changes in cortical connectivity and excitability that occur in this injury model, and postulate a mechanism to explain these findings.
Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Lateralidade Funcional/fisiologia , Agonistas de Receptores de GABA-A/farmacologia , Muscimol/farmacologia , Vias Neurais/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Membro Anterior , Lateralidade Funcional/efeitos dos fármacos , Masculino , Vias Neurais/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Extremidade SuperiorRESUMO
Ephedrine is thought to exert behavioural effects primarily through actions on the central nervous system. However, the neuromechanism underlying the effects of ephedrine addiction still remains unclear. Our study aimed to establish chronic ephedrine addiction models in rhesus monkeys and to investigate the neuromechanism of chronic ephedrine addiction using the behavioural methods combined with resting-state blood oxygenation level dependent-functional magnetic resonance imaging (BOLD-fMRI). Monkeys in the ephedrine addiction group (n = 6) received intramuscular injections of ephedrine using a dose escalation method, with a chronic model established in 8 weeks, while in the control group (n = 4), monkeys received a pure 0.9% saline injection. The weight and behaviors of the monkeys were observed throughout the treatment. All monkeys underwent the brain MR scans for two times (before treatment and after treatment had been discontinued). After molding, the weight of the ephedrine group was significantly reduced, while the weight of the control group increased significantly. Compared with the control group, the ephedrine addicted monkeys showed more abnormal behaviors related to addiction. In fMRI study, the ephedrine addicted monkeys showed more increased brain activation than that of the control group, mainly including the prefrontal cortex(PFC) and anterior cingulate cortex (ACC), the left ventral tegmental area(VTA), right insula, right amygdala, hippocampus, left thalamus, and left cerebellum.We hypothesize that the principal neuromechanism underlying chronic ephedrine addiction involves multiple abnormal brain neuron circuits, mainly in the PFC and the limbic system, and is closely related to addictive behaviors.
Assuntos
Comportamento Aditivo/induzido quimicamente , Comportamento Aditivo/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Estimulantes do Sistema Nervoso Central/toxicidade , Efedrina/toxicidade , Imageamento por Ressonância Magnética , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Lateralidade Funcional/efeitos dos fármacos , Processamento de Imagem Assistida por Computador , Macaca mulatta , Masculino , Oxigênio/sangue , DescansoRESUMO
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective therapy for motor symptoms of Parkinson's disease (PD); however, with repeated administration, as many as 94% of PD patients develop complications such as L-DOPA-induced dyskinesia. We previously demonstrated that EMD-281,014, a highly selective serotonin 2A (5-HT2A) receptor antagonist, reduces the severity of dyskinesia in the parkinsonian marmoset, without interfering with L-DOPA anti-parkinsonian benefit. Here, we assessed the effects of EMD-281,014 on L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat. We first determined the pharmacokinetic profile of EMD-281,014, to administer doses leading to clinically relevant plasma levels in the behavioural experiments. Dyskinetic 6-OHDA-lesioned rats were then administered EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) or vehicle in combination with L-DOPA and AIMs severity was evaluated. We also assessed the effect of EMD-281,014 on L-DOPA anti-parkinsonian action with the cylinder test. We found that the addition of EMD-281,014 (0.01, 0.03 and 0.1 mg/kg) to L-DOPA did not reduce AIMs severity (P > 0.05), when compared to vehicle. EMD-281,014 did not compromise L-DOPA anti-parkinsonian action. Our results suggest that the highly selective 5-HT2A receptor antagonist EMD-281,014 is well-tolerated by parkinsonian rats, but does not attenuate L-DOPA-induced AIMs. Our results highlight differences between rodent and primate models of PD when it comes to determining the anti-dyskinetic action of 5-HT2A receptor antagonists.
Assuntos
Discinesia Induzida por Medicamentos/tratamento farmacológico , Indóis/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Piperazinas/uso terapêutico , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Adrenérgicos/toxicidade , Animais , Antiparkinsonianos/efeitos adversos , Área Sob a Curva , Monoaminas Biogênicas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/etiologia , Feminino , Lateralidade Funcional/efeitos dos fármacos , Indóis/sangue , Levodopa/efeitos adversos , Oxidopamina/toxicidade , Doença de Parkinson Secundária/induzido quimicamente , Piperazinas/sangue , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Antagonistas do Receptor 5-HT2 de Serotonina/sangueRESUMO
INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative condition associated with aging characterized by loss of dopamine-producing neurons in the substantia nigra pars compacta and a reduction in dopamine levels in the striatum. PD is commonly treated using dopamine-replacement medication called levodopa. Levodopa has decreasing efficacy over time. Periods when levodopa is not effective at controlling symptoms of PD are called "OFF-time" or "medication-related motor fluctuations," (MRMF). One characteristic of PD is unilateral side of symptom onset. Previous studies have found that side of onset was associated with differential motor and cognitive PD-related symptoms. The main study objective was to examine differences in left and right onset PD patients and OFF-time as measured by the Movement Disorders Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part IV Sum Score and Part IV item scores. METHODS: 64 individuals with mild-moderate PD (age: M(SD)â¯=â¯68.72 (8.88)), years with PD: M(SD)â¯=â¯6.61 (5.05); Hoehn and Yahr stage Med (1st, 3rd quartile)â¯=â¯2.0 (2.0, 3.0) were assessed with the MDS-UPDRS parts I-IV. We conducted two-tailed independent sample t-tests to examine the differences between PD patients with left versus right onset. RESULTS: Right onset PD was significantly associated with more overall MRMF (pâ¯=â¯0.01), more OFF-time (pâ¯=â¯0.04), greater impact of motor fluctuations on daily life (pâ¯=â¯0.02) and more complex (unpredictable) MRMF (pâ¯=â¯0.01). CONCLUSION: People with right onset PD have more complications with levodopa treatment. Alternative and/or adjuvant treatments to levodopa may be particularly beneficial for those with right onset PD.
Assuntos
Progressão da Doença , Lateralidade Funcional/fisiologia , Testes de Estado Mental e Demência , Doença de Parkinson Secundária/diagnóstico , Doença de Parkinson/fisiopatologia , Índice de Gravidade de Doença , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/uso terapêutico , Feminino , Lateralidade Funcional/efeitos dos fármacos , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológicoRESUMO
Vestibular compensation is responsible for the spontaneous recovery of postural, locomotor, and oculomotor dysfunctions in patients with peripheral vestibular lesion or posterior circulation stroke. Mechanism investigation of vestibular compensation is of great importance in both facilitating recovery of vestibular function and understanding the postlesion functional plasticity in the adult CNS. Here, we report that postsynaptic histamine H1 receptor contributes greatly to facilitating vestibular compensation. The expression of H1 receptor is restrictedly increased in the ipsilesional rather than contralesional GABAergic projection neurons in the medial vestibular nucleus (MVN), one of the most important centers for vestibular compensation, in unilateral labyrinthectomized male rats. Furthermore, H1 receptor mediates an asymmetric excitation of the commissural GABAergic but not glutamatergic neurons in the ipsilesional MVN, which may help to rebalance bilateral vestibular systems and promote vestibular compensation. Selective blockage of H1 receptor in the MVN significantly retards the recovery of both static and dynamic vestibular symptoms following unilateral labyrinthectomy, and remarkably attenuates the facilitation of betahistine, whose effect has traditionally been attributed to its antagonistic action on the presynaptic H3 receptor, on vestibular compensation. These results reveal a previously unknown role for histamine H1 receptor in vestibular compensation and amelioration of vestibular motor deficits, as well as an involvement of H1 receptor in potential therapeutic effects of betahistine. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery in the CNS, but also a novel potential therapeutic target for vestibular disorders.SIGNIFICANCE STATEMENT Vestibular disorders manifest postural imbalance, nystagmus, and vertigo. Vestibular compensation is critical for facilitating recovery from vestibular disorders, and of great importance in understanding the postlesion functional plasticity in the adult CNS. Here, we show that postsynaptic H1 receptor in the medial vestibular nucleus (MVN) contributes greatly to the recovery of both static and dynamic symptoms following unilateral vestibular lesion. H1 receptor selectively mediates the asymmetric activation of commissural inhibitory system in the ipsilesional MVN and actively promotes vestibular compensation. The findings provide not only a new insight into the postlesion neuronal circuit plasticity and functional recovery of CNS, but also a novel potential therapeutic target for promoting vestibular compensation and ameliorating vestibular disorders.
Assuntos
Receptores Histamínicos H1/efeitos dos fármacos , Vestíbulo do Labirinto/fisiopatologia , Animais , beta-Histina/uso terapêutico , Orelha Interna , Lateralidade Funcional/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Neurônios/efeitos dos fármacos , Nistagmo Fisiológico/efeitos dos fármacos , Técnicas de Patch-Clamp , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Doenças Vestibulares/tratamento farmacológico , Núcleos Vestibulares/citologia , Núcleos Vestibulares/efeitos dos fármacos , Núcleos Vestibulares/fisiopatologia , Ácido gama-AminobutíricoAssuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/intoxicação , Antineoplásicos Imunológicos/intoxicação , Lateralidade Funcional/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Paralisia das Pregas Vocais/induzido quimicamente , Adenocarcinoma de Pulmão/patologia , Idoso de 80 Anos ou mais , Humanos , Neoplasias Pulmonares/patologia , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Prostaglandins are products of the cyclooxygenase pathway, which is implicated in Parkinson's disease (PD). Limited knowledge is available on mechanisms by which prostaglandins contribute to PD neurodegeneration. To address this gap, we focused on the prostaglandin PGD2/J2 signaling pathway, because PGD2 is the most abundant prostaglandin in the brain, and the one that increases the most under pathological conditions. Moreover, PGJ2 is spontaneously derived from PGD2. METHODS: In this study, we determined in rats the impact of unilateral nigral PGJ2-microinfusions on COX-2, lipocalin-type PGD2 synthase (L-PGDS), PGD2/J2 receptor 2 (DP2), and 15 hydroxyprostaglandin dehydrogenase (15-PGDH). Nigral dopaminergic (DA) and microglial distribution and expression levels of these key factors of the prostaglandin D2/J2 pathway were evaluated by immunohistochemistry. PGJ2-induced motor deficits were assessed with the cylinder test. We also determined whether oral treatment with ibuprofen improved the PD-like pathology induced by PGJ2. RESULTS: PGJ2 treatment induced progressive PD-like pathology in the rats. Concomitant with DA neuronal loss in the substantia nigra pars compacta (SNpc), PGJ2-treated rats exhibited microglia and astrocyte activation and motor deficits. In DA neurons, COX-2, L-PGDS, and 15-PGDH levels increased significantly in PGJ2-treated rats compared to controls, while DP2 receptor levels were unchanged. In microglia, DP2 receptors were basically non-detectable, while COX-2 and L-PGDS levels increased upon PGJ2-treatment, and 15-PGDH remained unchanged. 15-PGDH was also detected in oligodendrocytes. Notably, ibuprofen prevented most PGJ2-induced PD-like pathology. CONCLUSIONS: The PGJ2-induced rat model develops progressive PD pathology, which is a hard-to-mimic aspect of this disorder. Moreover, prevention of most PGJ2-induced PD-like pathology with ibuprofen suggests a positive feedback mechanism between PGJ2 and COX-2 that could lead to chronic neuroinflammation. Notably, this is the first study that analyzes the nigral dopaminergic and microglial distribution and levels of factors of the PGD2/J2 signaling pathway in rodents. Our findings support the notions that upregulation of COX-2 and L-PGDS may be important in the PGJ2 evoked PD-like pathology, and that neuronal DP2 receptor antagonists and L-PGDS inhibitors may be novel pharmacotherapeutics to relieve neuroinflammation-mediated neurodegeneration in PD, circumventing the adverse side effects of cyclooxygenase inhibitors.