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1.
Brain Behav ; 14(7): e3605, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38956819

RESUMO

BACKGROUND: High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor symptoms of Parkinson's disease (PD). However, whether the high frequency of rTMS positively correlates to the improvement of motor symptoms of PD is still undecided. By controlling for other parameters, a disease animal model may be useful to compare the neuroprotective effects of different high frequencies of rTMS. OBJECTIVE: The current exploratory study was designed to compare the protective effects of four common high frequencies of rTMS (5, 10, 15, and 20 Hz) and iTBS (a special form of high-frequency rTMS) and explore the optimal high-frequency rTMS on an animal PD model. METHODS: Following high frequencies of rTMS application (twice a week for 5 weeks) in a MPTP/probenecid-induced chronic PD model, the effects of the five protocols on motor behavior as well as dopaminergic neuron degeneration levels were identified. The underlying molecular mechanisms were further explored. RESULTS: We found that all the high frequencies of rTMS had protective effects on the motor functions of PD models to varying degrees. Among them, the 10, 15, and 20 Hz rTMS interventions induced comparable preservation of motor function through the protection of nigrostriatal dopamine neurons. The enhancement of brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2) and the suppression of TNF-α and IL-1ß in the nigrostriatum were involved in the process. The efficacy of iTBS was inferior to that of the above three protocols. The effect of 5 Hz rTMS protocol was weakest. CONCLUSIONS: Combined with the results of the present study and the possible side effects induced by rTMS, we concluded that 10 Hz might be the optimal stimulation frequency for preserving the motor functions of PD models using rTMS treatment.


Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos , Probenecid , Estimulação Magnética Transcraniana , Animais , Estimulação Magnética Transcraniana/métodos , Camundongos , Masculino , Probenecid/farmacologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/terapia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Motor/metabolismo , Córtex Motor/fisiopatologia , Neurônios Dopaminérgicos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Interleucina-1beta/metabolismo , Substância Negra/metabolismo , Corpo Estriado/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Intoxicação por MPTP/terapia , Intoxicação por MPTP/prevenção & controle , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/fisiopatologia , Atividade Motora/fisiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia
2.
Afr Health Sci ; 24(1): 206-212, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38962328

RESUMO

Introduction: Trazodone is an antidepressant agent approved for treating major depressive disorders and is also prescribed for insomnia due to its sedative effect. In a few cases, trazodone was associated with parkinsonism. Herein, we describe a case of parkinsonism after a brief exposure to a moderate dose of trazodone. Objective: To describe a case of a patient with trazodone-induced parkinsonism in which the diagnosis was suspected after the exclusion of other common and serious causes. Methods: A case report of trazodone-induced parkinsonism. Clinical Case: A 58-year-old male with sleeping problems was prescribed trazodone 50 mg daily at bedtime. The subject doubled the dosage without medical advice a week later. After 14 days of trazodone treatment, he started to experience difficulty in moving his upper limbs and recurrent falling. Neuroimaging, electrodiagnostic studies, and laboratory exams were unremarkable. Trazodone was discontinued, and the patient fully recovered. Noteworthy, the patient developed a recurrence of the motor symptoms with trazodone-rechallenge. Conclusion: Our case showed reversibly induced parkinsonism after a short intake of a moderate dose of trazodone which was prescribed for insomnia. The patient had a complete recovery after trazodone withdrawal. Noteworthy, the symptoms recurred upon trazodone-rechallenge.


Assuntos
Trazodona , Humanos , Trazodona/efeitos adversos , Masculino , Pessoa de Meia-Idade , Antidepressivos de Segunda Geração/efeitos adversos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente
3.
Brain Res Bull ; 214: 110989, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38825252

RESUMO

Parkinson's disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16 S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16 S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.


Assuntos
Neurônios Dopaminérgicos , Molécula 1 de Adesão Intercelular , Camundongos Endogâmicos C57BL , Animais , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Masculino , Modelos Animais de Doenças , Doenças Neuroinflamatórias/metabolismo , Microbioma Gastrointestinal/fisiologia , Microbioma Gastrointestinal/efeitos dos fármacos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Inflamação/metabolismo , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Microglia/metabolismo , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/patologia
4.
Neurobiol Dis ; 198: 106559, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38852753

RESUMO

Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.


Assuntos
Discinesia Induzida por Medicamentos , Levodopa , Oxidopamina , Animais , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/farmacologia , Oxidopamina/toxicidade , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Antiparkinsonianos/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Receptores 5-HT4 de Serotonina/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Piridinas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Piperidinas , Pirimidinas
5.
Artigo em Inglês | MEDLINE | ID: mdl-38865235

RESUMO

Freezing of gait (FoG) is a prevalent symptom among individuals with Parkinson's disease and related disorders. FoG detection from videos has been developed recently; however, the process requires using videos filmed within a controlled environment. We attempted to establish an automatic FoG detection method from videos taken in uncontrolled environments such as in daily clinical practices. Motion features of 16 patients were extracted from timed-up-and-go test in 109 video data points, through object tracking and three-dimension pose estimation. These motion features were utilized to form the FoG detection model, which combined rule-based and machine learning-based models. The rule-based model distinguished the frames in which the patient was walking from those when the patient has stopped, using the pelvic position coordinates; the machine learning-based model distinguished between FoG and stop using a combined one-dimensional convolutional neural network and long short-term memory (1dCNN-LSTM). The model achieved a high intraclass correlation coefficient of 0.75-0.94 with a manually-annotated duration of FoG and %FoG. This method is novel as it combines object tracking, 3D pose estimation, and expert-guided feature selection in the preprocessing and modeling phases, enabling FoG detection even from videos captured in uncontrolled environments.


Assuntos
Transtornos Neurológicos da Marcha , Aprendizado de Máquina , Redes Neurais de Computação , Gravação em Vídeo , Humanos , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/etiologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Algoritmos , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/fisiopatologia , Memória de Curto Prazo , Idoso de 80 Anos ou mais
6.
Sci Rep ; 14(1): 13229, 2024 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-38853162

RESUMO

X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential clinical trial endpoint. Wearable sensor data was collected from 10 symptomatic XDP patients and 3 healthy controls during a standardized examination. Disease severity was assessed with the Unified Parkinson's Disease Rating Scale Part 3 (MDS-UPDRS) and Burke-Fahn-Marsden dystonia scale (BFM). We collected sensor data during the performance of specific MDS-UPDRS/BFM upper- and lower-limb motor tasks, and derived data features suitable to estimate clinical scores using machine learning (ML). XDP patients were at varying stages of disease and clinical severity. ML-based algorithms estimated MDS-UPDRS scores (parkinsonism) and dystonia-specific data features with a high degree of accuracy. Gait spatio-temporal parameters had high discriminatory power in differentiating XDP patients with different MDS-UPDRS scores from controls, XDP freezing of gait, and dystonic/non-dystonic gait. These analyses suggest the feasibility of using wearable sensor data for deriving reliable clinical score estimates associated with both parkinsonian and dystonic features in a complex, combined movement disorder and the utility of motion sensors in quantifying clinical examination.


Assuntos
Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Aprendizado de Máquina , Dispositivos Eletrônicos Vestíveis , Humanos , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Masculino , Adulto , Pessoa de Meia-Idade , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/diagnóstico , Índice de Gravidade de Doença , Feminino , Marcha
7.
Elife ; 122024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38940422

RESUMO

Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline (NA) reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both NA and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.


Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos , Núcleo Dorsal da Rafe , Oxidopamina , Transtornos Parkinsonianos , Neurônios Serotoninérgicos , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Neurônios Serotoninérgicos/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/efeitos dos fármacos , Camundongos , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Masculino , Camundongos Endogâmicos C57BL , Desipramina/farmacologia , Norepinefrina/metabolismo
9.
Age Ageing ; 53(5)2024 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-38783753

RESUMO

BACKGROUND AND OBJECTIVES: People with parkinsonism who are older, living in a care home, with frailty, multimorbidity or impaired capacity to consent are under-represented in research, limiting its generalisability. We aimed to evaluate more inclusive recruitment strategies. METHODS: From one UK centre, we invited people with parkinsonism to participate in a cross-sectional study. Postal invitations were followed by telephone reminders and additional support to facilitate participation. Personal consultees provided information on the views regarding research participation of adults with impaired capacity. These approaches were evaluated: (i) using external data from the Parkinson's Real World Impact assesSMent (PRISM) study and Clinical Practice Research Datalink (CPRD), a sample of all cases in UK primary care, and (ii) comparing those recruited with or without intensive engagement. RESULTS: We approached 1,032 eligible patients, of whom 542 (53%) consented and 477 (46%) returned questionnaires. The gender ratio in PRIME-UK (65% male) closely matched CPRD (61% male), unlike in the PRISM sample (46%). Mean age of PRIME participants was 75.9 (SD 8.5) years, compared to 75.3 (9.5) and 65.4 (8.9) years for CPRD and PRISM, respectively. More intensive engagement enhanced recruitment of women (13.3%; 95% CI 3.8, 22.9%; P = 0.005), care home residents (6.2%; 1.1, 11.2%; P = 0.004), patients diagnosed with atypical parkinsonism (13.7%; 5.4, 19.9%; P < 0.001), and those with a higher frailty score (mean score 0.2, 0.1, 0.2; P < 0.001). CONCLUSIONS: These recruitment strategies resulted in a less biased and more representative sample, with greater inclusion of older people with more complex parkinsonism.


Assuntos
Disfunção Cognitiva , Fragilidade , Multimorbidade , Doença de Parkinson , Seleção de Pacientes , Humanos , Masculino , Feminino , Idoso , Estudos Transversais , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Disfunção Cognitiva/diagnóstico , Reino Unido/epidemiologia , Fragilidade/epidemiologia , Fragilidade/psicologia , Fragilidade/diagnóstico , Idoso de 80 Anos ou mais , Doença de Parkinson/psicologia , Doença de Parkinson/epidemiologia , Doença de Parkinson/diagnóstico , Idoso Fragilizado/psicologia , Idoso Fragilizado/estatística & dados numéricos , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/psicologia , Transtornos Parkinsonianos/diagnóstico
10.
Biochem Soc Trans ; 52(3): 1275-1291, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38813865

RESUMO

Parkinsonism is the primary type of movement disorder in adults, encompassing a set of clinical symptoms, including rigidity, tremors, dystonia, bradykinesia, and postural instability. These symptoms are primarily caused by a deficiency in dopamine (DA), an essential neurotransmitter in the brain. Currently, the DA precursor levodopa (synthetic L-DOPA) is the standard medication to treat DA deficiency, but it only addresses symptoms rather than provides a cure. In this review, we provide an overview of disorders associated with DA dysregulation and deficiency, particularly Parkinson's disease and rare inherited disorders leading predominantly to dystonia and/or parkinsonism, even in childhood. Although levodopa is relatively effective for the management of motor dysfunctions, it is less effective for severe forms of parkinsonism and is also associated with side effects and a loss of efficacy over time. We present ongoing efforts to reinforce the effect of levodopa and to develop innovative therapies that target the underlying pathogenic mechanisms affecting DA synthesis and transport, increasing neurotransmission through disease-modifying approaches, such as cell-based therapies, nucleic acid- and protein-based biologics, and small molecules.


Assuntos
Dopamina , Levodopa , Doença de Parkinson , Humanos , Dopamina/metabolismo , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Animais , Transporte Biológico
11.
Parkinsonism Relat Disord ; 124: 106976, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38718479

RESUMO

Neurodevelopmental disorders with early-onset parkinsonism have diverse genetic aetiologies and can mimic Parkinson's disease. We report the clinical evaluation and neuroimaging studies of a woman with intellectual disability and levodopa-responsive akinetic rigid parkinsonism. Whole-genome sequencing of family trio identified a de novo missense variant in PPP2R5D in the proband.


Assuntos
Mutação de Sentido Incorreto , Transtornos Parkinsonianos , Proteína Fosfatase 2 , Humanos , Feminino , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/diagnóstico por imagem , Proteína Fosfatase 2/genética , Idade de Início , Adulto , Heterozigoto , Deficiência Intelectual/genética , Linhagem
13.
Int J Mol Sci ; 25(10)2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38791326

RESUMO

Chronic environmental exposure to toxic heavy metals, which often occurs as a mixture through occupational and industrial sources, has been implicated in various neurological disorders, including Parkinsonism. Vanadium pentoxide (V2O5) typically presents along with manganese (Mn), especially in welding rods and high-capacity batteries, including electric vehicle batteries; however, the neurotoxic effects of vanadium (V) and Mn co-exposure are largely unknown. In this study, we investigated the neurotoxic impact of MnCl2, V2O5, and MnCl2-V2O5 co-exposure in an animal model. C57BL/6 mice were intranasally administered either de-ionized water (vehicle), MnCl2 (252 µg) alone, V2O5 (182 µg) alone, or a mixture of MnCl2 (252 µg) and V2O5 (182 µg) three times a week for up to one month. Following exposure, we performed behavioral, neurochemical, and histological studies. Our results revealed dramatic decreases in olfactory bulb (OB) weight and levels of tyrosine hydroxylase, dopamine, and 3,4-dihydroxyphenylacetic acid in the treatment groups compared to the control group, with the Mn/V co-treatment group producing the most significant changes. Interestingly, increased levels of α-synuclein expression were observed in the substantia nigra (SN) of treated animals. Additionally, treatment groups exhibited locomotor deficits and olfactory dysfunction, with the co-treatment group producing the most severe deficits. The treatment groups exhibited increased levels of the oxidative stress marker 4-hydroxynonenal in the striatum and SN, as well as the upregulation of the pro-apoptotic protein PKCδ and accumulation of glomerular astroglia in the OB. The co-exposure of animals to Mn/V resulted in higher levels of these metals compared to other treatment groups. Taken together, our results suggest that co-exposure to Mn/V can adversely affect the olfactory and nigral systems. These results highlight the possible role of environmental metal mixtures in the etiology of Parkinsonism.


Assuntos
Compostos de Manganês , Manganês , Camundongos Endogâmicos C57BL , Vanádio , Animais , Camundongos , Manganês/toxicidade , Vanádio/toxicidade , Masculino , Bulbo Olfatório/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/patologia , Dopamina/metabolismo , Compostos de Vanádio , Estresse Oxidativo/efeitos dos fármacos , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , alfa-Sinucleína/metabolismo , Cloretos/toxicidade , Cloretos/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Aldeídos/metabolismo , Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Modelos Animais de Doenças , Ácido 3,4-Di-Hidroxifenilacético/metabolismo
14.
J Ethnopharmacol ; 332: 118363, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-38763373

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum, a renowned tonic traditional Chinese medicine, is widely recognized for the exceptional activity in soothing nerves and nourishing the brain. It has been extensively employed to alleviate various neurological disorders, notably Parkinson's disease (PD). AIM OF THE STUDY: To appraise the antiparkinsonian effect of GAA, the main bioactive constituent of G. lucidum, and clarify the molecular mechanism through the perspective of ferritinophagy-mediated dopaminergic neuron ferroptosis. MATERIALS AND METHODS: PD mouse and cell models were established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP+), respectively. Cell viability, behavioral tests and immunofluorescence analysis were performed to evaluate the neurotoxicity, motor dysfunction and dopaminergic loss, respectively. Biochemical assay kits were used to determine the levels of iron, lipid reactive oxygen species (ROS), malondialdehyde (MDA), total ROS and glutathione (GSH). Western blot and immunofluorescence were applied to detect the expressions of nuclear receptor co-activator 4 (NCOA4), ferritin heavy chain 1 (FTH1), p62 and LC3B. Additionally, NCOA4-overexpressing plasmid vector was constructed to verify the inhibitory effect of GAA on the neurotoxicity and ferroptosis-related parameters in PD models. RESULTS: GAA significantly mitigated MPP+/MPTP-induced neurotoxicity, motor dysfunction and dopaminergic neuron loss (p<0.01 or p<0.05). In contrast to MPP+/MPTP treatment, GAA treatment decreased the levels of iron, MDA, lipid and total ROS, while increasing the GSH level. GAA also reduced the levels of NCOA4 and LC3B, and enhanced the expressions of FTH1 and p62 in PD models (p<0.01 or p<0.05). However, the protective effect of GAA against the neurotoxicity, NCOA4-mediated ferritinophagy and ferroptosis in PD model was abolished by the overexpression of NCOA4 (p<0.01). CONCLUSION: GAA exerted a protective effect on PD, and this effect was achieved by suppressing dopaminergic neuron ferroptosis through the inhibition of NCOA4-mediated ferritinophagy.


Assuntos
Neurônios Dopaminérgicos , Ferritinas , Ferroptose , Camundongos Endogâmicos C57BL , Coativadores de Receptor Nuclear , Animais , Ferroptose/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Coativadores de Receptor Nuclear/metabolismo , Camundongos , Masculino , Ferritinas/metabolismo , Fármacos Neuroprotetores/farmacologia , Autofagia/efeitos dos fármacos , Antiparkinsonianos/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/induzido quimicamente , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Modelos Animais de Doenças
15.
Acta Neuropathol Commun ; 12(1): 79, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773545

RESUMO

Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.


Assuntos
Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores , Niacinamida , Células Ganglionares da Retina , Animais , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , Niacinamida/farmacologia , Niacinamida/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Masculino , Camundongos , Administração Oral , Injeções Intravítreas , Modelos Animais de Doenças , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/tratamento farmacológico , Intoxicação por MPTP/patologia , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/tratamento farmacológico
17.
Brain Behav Immun ; 119: 851-866, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38750702

RESUMO

Cognitive impairment in Parkinson's disease is considered an indicator of the prodromal stages of this condition, occurring prior to the onset of classic and pathognomonic motor symptoms. Among other factors, neuroinflammation is increasingly recognized as a potential mediator of this neurodegenerative process, and glial cells are directly involved. However, the use of neurotrophic factors is associated with neuroprotection and cognitive improvements. Among all those factors, insulin-like growth factor 1 (IGF-1) has attracted considerable attention. In this study, we aimed to investigate the effect of IGF-1 gene therapy in an early animal model of 6-hydroxidopamine (6-OHDA)- induced parkinsonism. For this purpose, we employed male Wistar rats. The animals were first divided into two groups according to the bilateral injection into de Caudate Putamen unit (CPu):(a) VEH group (vehicle solution) and (b) 6-OHDA group (neurotoxic solution). After that, the animals in each group were divided, according to the bilateral injection into the dorsal hippocampus, in a control group (who received a control virus RAd-DSRed) and an experimental group (who received a therapeutic virus (RAd-IGF1). After three weeks of exposure to 6-OHDA, our study showed that IGF-1 gene therapy improved cognitive deficits related to short-term and spatial working memory, it also increased expression levels of tyrosine hydroxylase in the CPu. In addition, the therapy resulted in significant changes in several parameters (area, perimeter, roundness, ramification, and skeleton ́s analyses) related to microglia and astrocyte phenotypes, particularly in the CPu and dorsal hippocampal areas. Our data support the use of IGF-1 as a therapeutic molecule for future gene transfer interventions, that will contribute to a better understanding of the mechanisms correlating cognitive function and inflammatory process.


Assuntos
Modelos Animais de Doenças , Terapia Genética , Fator de Crescimento Insulin-Like I , Transtornos da Memória , Transtornos Parkinsonianos , Ratos Wistar , Memória Espacial , Animais , Masculino , Fator de Crescimento Insulin-Like I/metabolismo , Ratos , Terapia Genética/métodos , Transtornos da Memória/metabolismo , Transtornos da Memória/terapia , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/terapia , Oxidopamina , Inflamação/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hipocampo/metabolismo , Dopamina/metabolismo
18.
Mov Disord Clin Pract ; 11(6): 613-625, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38693679

RESUMO

BACKGROUND: As the diagnosis of Parkinson's disease (PD) is fundamentally clinical, the usefulness of ioflupane (123I) single-photon emission computed tomography (SPECT) or DaTSCAN as a diagnostic tool has been a matter of debate for years. The performance of DaTSCAN is generally recommended in the follow-up of patients with a clinically uncertain diagnosis, especially in those with a suspected essential tremor, drug-induced parkinsonism, or vascular parkinsonism. However, there is a dearth of DaTSCAN findings regarding neurodegenerative parkinsonisms besides PD and atypical parkinsonisms. To date, a specific nigrostriatal dopamine uptake pattern that would help differentiate PD from the most frequent atypical parkinsonisms is yet to be described. This fact is further complicated by the possible visualization of abnormalities in the uptake pattern in patients with rarer neurodegenerative parkinsonisms. OBJECTIVES: We aimed to summarize the current literature regarding DaTSCAN findings in patients with rare neurodegenerative parkinsonisms. METHODS: The PubMed database was systematically screened for studies in English or Spanish up to October 15, 2023, using search terms "DaTSCAN", "ioflupane", "DaT-SPECT", "123I-FP-CIT SPECT", "dopamine transporter imaging", and "[123I] FP-CIT SPECT". Duplicated publications and studies regarding PD, atypical parkinsonisms, dystonia-parkinsonism, essential tremor, and parkinsonism due to non-degenerative causes were excluded. RESULTS: The obtained results were reviewed and summarized, including DaTSCAN findings in fragile X-associated tremor/ataxia syndrome, prion diseases, Huntington's disease, spinocerebellar ataxia, hereditary spastic paraparesis, metabolic disorders, and other diseases (anti-IgLON5 disease, ring chromosome 20 syndrome, chorea-acanthocytosis, and neuronal ceroid lipofuscinosis). CONCLUSIONS: This review highlights the need to determine in the future the utility and cost-effectiveness of DaTSCAN, both as a diagnostic and a prognostic tool, in patients with parkinsonian symptoms in rare neurodegenerative diseases.


Assuntos
Transtornos Parkinsonianos , Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/metabolismo , Tropanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo
19.
Neurology ; 102(11): e209453, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38759132

RESUMO

BACKGROUND AND OBJECTIVES: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism. METHODS: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism. RESULTS: All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%). DISCUSSION: DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Feminino , Idoso , Masculino , Estudos Retrospectivos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/patologia , Atrofia de Múltiplos Sistemas/metabolismo , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/metabolismo , Idoso de 80 Anos ou mais , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Estudos de Coortes , Degeneração Corticobasal/diagnóstico por imagem , Degeneração Corticobasal/metabolismo , Dopamina/metabolismo , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/patologia , Sensibilidade e Especificidade , Imageamento Dopaminérgico
20.
BMJ Open ; 14(5): e081317, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38692728

RESUMO

INTRODUCTION: Gait and mobility impairment are pivotal signs of parkinsonism, and they are particularly severe in atypical parkinsonian disorders including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). A pilot study demonstrated a significant improvement of gait in patients with MSA of parkinsonian type (MSA-P) after physiotherapy and matching home-based exercise, as reflected by sensor-based gait parameters. In this study, we aim to investigate whether a gait-focused physiotherapy (GPT) and matching home-based exercise lead to a greater improvement of gait performance compared with a standard physiotherapy/home-based exercise programme (standard physiotherapy, SPT). METHODS AND ANALYSIS: This protocol was deployed to evaluate the effects of a GPT versus an active control undergoing SPT and matching home-based exercise with regard to laboratory gait parameters, physical activity measures and clinical scales in patients with Parkinson's disease (PD), MSA-P and PSP. The primary outcomes of the trial are sensor-based laboratory gait parameters, while the secondary outcome measures comprise real-world derived parameters, clinical rating scales and patient questionnaires. We aim to enrol 48 patients per disease group into this double-blind, randomised-controlled trial. The study starts with a 1 week wearable sensor-based monitoring of physical activity. After randomisation, patients undergo a 2 week daily inpatient physiotherapy, followed by 5 week matching unsupervised home-based training. A 1 week physical activity monitoring is repeated during the last week of intervention. ETHICS AND DISSEMINATION: This study, registered as 'Mobility in Atypical Parkinsonism: a Trial of Physiotherapy (Mobility_APP)' at clinicaltrials.gov (NCT04608604), received ethics approval by local committees of the involved centres. The patient's recruitment takes place at the Movement Disorders Units of Innsbruck (Austria), Erlangen (Germany), Lausanne (Switzerland), Luxembourg (Luxembourg) and Bolzano (Italy). The data resulting from this project will be submitted to peer-reviewed journals, presented at international congresses and made publicly available at the end of the trial. TRIAL REGISTRATION NUMBER: NCT04608604.


Assuntos
Terapia por Exercício , Transtornos Parkinsonianos , Modalidades de Fisioterapia , Humanos , Terapia por Exercício/métodos , Transtornos Parkinsonianos/reabilitação , Transtornos Parkinsonianos/terapia , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como Assunto , Marcha , Doença de Parkinson/reabilitação , Doença de Parkinson/terapia , Atrofia de Múltiplos Sistemas/reabilitação , Atrofia de Múltiplos Sistemas/terapia , Paralisia Supranuclear Progressiva/terapia , Paralisia Supranuclear Progressiva/reabilitação , Serviços de Assistência Domiciliar , Idoso , Masculino , Feminino , Transtornos Neurológicos da Marcha/reabilitação , Transtornos Neurológicos da Marcha/etiologia
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