RESUMEN
Intellectual drug doping in athletics by using stimulants that affect central nervous system functions has been diversified. Stimulants are regulated by the World Anti-Doping Agency according to their levels of urinary concentration. Positron emission tomography could evaluate how stimulants affect central nervous system functions. We aimed to evaluate the effect of stimulants on brain function by examining the difference in brain dopamine transporter occupancy by PET after administration of dl-methylephedrine or pseudoephedrine at the clinical maximum daily dose. Four PET scans without and with drug administration (placebo, dl-methylephedrine 150 mg and pseudoephedrine 240 mg) were performed. The concentrations of dl-methylephedrine and pseudoephedrine in plasma and urine were measured. DAT occupancies in the striatum with placebo, dl-methylephedrine and pseudoephedrine were calculated by PET images. The urinary concentration of dl-methylephedrine (12.7 µg/mL) exceeded the prohibited concentration (10 µg/mL), but the DAT occupancy with dl-methylephedrine (6.1%) did not differ (p = 0.92) from that with placebo (6.2%). By contrast, although the urinary concentration of pseudoephedrine (144.8 µg/mL) was below the prohibited concentration (150 µg/mL), DAT occupancy with pseudoephedrine was 18.4%, which was higher than that with placebo (p = 0.009). At the maximum clinical dose, dl-methylephedrine was shown to have weaker effects on brain function than pseudoephedrine.
Asunto(s)
Encéfalo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Tomografía de Emisión de Positrones , Seudoefedrina , Humanos , Masculino , Tomografía de Emisión de Positrones/métodos , Seudoefedrina/farmacología , Seudoefedrina/administración & dosificación , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Adulto , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Adulto Joven , Estimulantes del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/orina , Estimulantes del Sistema Nervioso Central/administración & dosificación , Doping en los Deportes/prevención & control , Femenino , Efedrina/análogos & derivadosRESUMEN
Combination antiretroviral therapy (cART) has dramatically reduced mortality in people with human immunodeficiency virus (HIV), but it does not completely eradicate the virus from the brain. Patients with long-term HIV-1 infection often show neurocognitive impairment, which severely affects the quality of life of those infected. Methamphetamine (METH) users are at a significantly higher risk of contracting HIV-1 through behaviors such as engaging in high-risk sex or sharing needles, which can lead to transmission of the virus. In addition, HIV-1-infected individuals who abuse METH exhibit higher viral loads and more severe cognitive dysfunction, suggesting that METH exacerbates the neurotoxicity associated with HIV-1. Therefore, this review focuses on various mechanisms underlying METH and HIV-1 infection co-induced neurotoxicity and existing interventions targeting the sigma 1 receptor, dopamine transporter protein, and other relevant targets are explored. The findings of this review are envisaged to systematically establish a theoretical framework for METH abuse and HIV-1 infection co-induced neurotoxicity, and to suggest novel clinical treatment targets.
Asunto(s)
Infecciones por VIH , VIH-1 , Metanfetamina , Humanos , Metanfetamina/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , VIH-1/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Animales , Trastornos Relacionados con Anfetaminas/complicaciones , Trastornos Relacionados con Anfetaminas/terapia , Receptor Sigma-1 , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismoRESUMEN
Isolated REM Sleep Behavior Disorder (iRBD) is considered a prodrome of Parkinson's disease (PD). We investigate whether the potentially disease-modifying compound acetyl-DL-leucine (ADLL; 5 g/d) has an effect on prodromal PD progression in 2 iRBD-patients. Outcome parameters are RBD-severity sum-score (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic "Parkinson-Disease-related-Pattern (PDRP)"-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). After 3 weeks ADLL-treatment, the RBD-SS-3 drops markedly in both patients and remains reduced for >18 months of ADLL-treatment. In patient 1 (female), the DAT-SPECT putaminal binding ratio (PBR) decreases in the 5 years pretreatment from normal (1.88) to pathological (1.22) and the patient's FDG-PET-PDRP-z-score rises from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increases to 1.67 and the FDG-PET-PDRP-z-score stabilizes at 3.18. Similar results are seen in patient 2 (male): his DAT-SPECT-PBR rises from a pretreatment value of 1.42 to 1.72 (close to normal) and the FDG-PET-PDRP-z-score decreases from 1.02 to 0.30 after 18 months of ADLL-treatment. These results support exploration of whether ADLL may have disease-modifying properties in prodromal PD.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Leucina , Enfermedad de Parkinson , Tomografía de Emisión de Positrones , Trastorno de la Conducta del Sueño REM , Tomografía Computarizada de Emisión de Fotón Único , Humanos , Femenino , Trastorno de la Conducta del Sueño REM/metabolismo , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Trastorno de la Conducta del Sueño REM/tratamiento farmacológico , Masculino , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Tomografía de Emisión de Positrones/métodos , Leucina/metabolismo , Leucina/análogos & derivados , Anciano , Persona de Mediana Edad , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Fluorodesoxiglucosa F18/metabolismo , Cuerpo Estriado/metabolismo , Cuerpo Estriado/diagnóstico por imagenRESUMEN
OBJECTIVE: Dementia with Lewy bodies (DLB) is recognized as the second most common cause of degenerative dementia in older people with Alzheimer's disease (AD), and distinguishing between these 2 diseases may be challenging in clinical practice. However, accurate differentiation is important because these 2 diseases have different prognoses and require different care. Recently, several studies have reported that neuromelanin-sensitive MRI can detect neurodegeneration in the substantia nigra pars compacta (SNc). DLB patients are considered to demonstrate degeneration and a reduction of dopaminergic neurons in the SNc. Therefore, neuromelanin-sensitive MRI may be useful for the diagnosis of DLB. Therefore, in this study, we aimed to investigate the usefulness of neuromelanin-sensitive MRI in the distinguishing DLB from AD. METHODS: A total of 21 probable DLB and 22 probable AD patients were enrolled. All participants underwent both DaT-SPECT and neuromelanin-sensitive MRI. A combined model of neuromelanin-sensitive MRI and Dopamine transporter single-photon emission computed tomography (DaT-SPECT) was created using logistic regression analysis (forced entry method). RESULTS: There was no difference in the diagnostic utility of neuromelanin-sensitive MRI and DaT-SPECT in distinguishing DLB from AD. There was no significant correlation between the results of neuromelanin-sensitive MRI and DaT-SPECT in DLB patients. The combination of neuromelanin-sensitive MRI and DaT-SPECT demonstrated higher diagnostic performance in distinguishing between DLB and AD compared with neuromelanin-sensitive MRI alone. Additionally, although the combination of both modalities showed a larger AUC compared with DaT-SPECT alone, the difference was not statistically significant. CONCLUSIONS: Neuromelanin-sensitive MRI may be equally or even more useful than DaT-SPECT in the clinical differentiation of DLB from AD. Furthermore, the combination of neuromelanin-sensitive MRI and DaT-SPECT may be a highly sensitive imaging marker for distinguishing DLB from AD.
Asunto(s)
Enfermedad por Cuerpos de Lewy , Imagen por Resonancia Magnética , Melaninas , Tomografía Computarizada de Emisión de Fotón Único , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/diagnóstico , Melaninas/metabolismo , Femenino , Anciano , Masculino , Imagen por Resonancia Magnética/métodos , Anciano de 80 o más Años , Tomografía Computarizada de Emisión de Fotón Único/métodos , Diagnóstico Diferencial , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismoRESUMEN
INTRODUCTION: Personality disorders (PD) are characterized by socially dysfunctional behavioral patterns that affect patients and show higher incidence rates within families. Substance abuse disorders (SAD) are exemplified by extensive and prolonged use of substances, including alcohol, nicotine, or illegal drugs. Genetic predisposition for both PD and SAD has been reported to involve gene variants regulating dopaminergic pathways. Yet, discrepancy among reported results necessitates further elucidation of potential hereditary-related risk factors. Because both disorders impose a societal burden, knowledge on the impact of certain genetic backgrounds on these diseases could help develop evidence-based strategies for efficacious treatment approaches. MATERIALS AND METHODS: In the present study a systematic review was performed, and the association between dopamine transporter gene polymorphism (SLC6A3), particularly rs28363170 entailing a 40-bp variable number tandem repeat, and PD as well as SAD was investigated recruiting meta-analysis approach. RESULTS: Initial literature search for PD yielded 1577, from which nine fulfilled eligibility criteria to be used in a meta-analysis including 729 cases and 2113 controls. From the 934 studies retrieved for SAD, only 29 articles with 5221 cases and 4822 controls were used for meta-analysis. A statistically significant association was seen between rs28363170 (for the 9-repeat allele) and PD in European populations according to the co-dominant mode of inheritance. For SAD no statistically significant correlation under any mode of inheritance was observed. There was no indication of time-trend phenomena. CONCLUSION: Our findings demonstrate the association of SLC6A3 gene polymorphism with PD, thus underling the need to understand neurobiological mechanisms inherent to the above disorders to guide treatment strategies under the perspective of personalized medicine.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Predisposición Genética a la Enfermedad , Trastornos de la Personalidad , Trastornos Relacionados con Sustancias , Humanos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Trastornos Relacionados con Sustancias/genética , Trastornos de la Personalidad/genética , Polimorfismo de Nucleótido Simple/genética , Estudios de Asociación Genética/métodosRESUMEN
The accumulation of iron in dopaminergic neurons can cause oxidative stress and dopaminergic neuron degeneration. Iron chelation therapy may reduce dopaminergic neurodegeneration, but chelators should be targeted towards dopaminergic cells. In this work, two series of compounds based on 8-hydroxyquinoline and deferiprone, iron chelators that have amphetamine-like structures, have been designed, synthesized and characterized. Each of these compounds chelated iron ions in aqueous solution. The hydroxyquinoline-based compounds exhibited stronger iron-binding constants than those of the deferiprone derivatives. The hydroxyquinoline-based compounds also exhibited greater free radical scavenging activities compared to the deferiprone derivatives. Molecular dynamics simulations showed that the hydroxyquinoline-based compounds generally bound well within human dopamine transporter cavities. Thus, these compounds are excellent candidates for future exploration as drugs against diseases that are affected by iron-induced dopaminergic neuron damage, such as Parkinson's disease.
Asunto(s)
Clioquinol , Deferiprona , Quelantes del Hierro , Hierro , Deferiprona/farmacología , Deferiprona/química , Quelantes del Hierro/farmacología , Quelantes del Hierro/química , Humanos , Hierro/química , Hierro/metabolismo , Clioquinol/farmacología , Clioquinol/química , Simulación de Dinámica Molecular , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/química , Estructura Molecular , Anfetamina/química , Anfetamina/farmacologíaAsunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Enfermedad de Parkinson , Piel , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/diagnóstico por imagen , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Piel/patología , Piel/metabolismo , Biopsia , Cuerpos de Inclusión/patología , Cuerpos de Inclusión/metabolismo , Sinucleínas/metabolismo , Imágenes DopaminérgicasRESUMEN
INTRODUCTION: Gerstmann-Sträussler-Scheinker disease (GSS) is an autosomal-dominant inherited prion disease most often associated with the human prion protein gene (PRNP)-P102L mutation. Although patients manifest considerable phenotypic heterogeneity, the involvement of the nigrostriatal system has not been well-studied. METHODS: We performed dopamine transporter single-photon emission computed tomography (DAT-SPECT) using 123I-ioflupane to investigate the nigrostriatal system function in nine patients with the PRNP-P102L mutation. We also examined the pathological findings in another patient whose predominant feature was ataxia and who died 5 years after disease onset. RESULTS: Striatum uptake of 123I-ioflupane indicated by specific binding ratio (SBR) values was significantly reduced in two patients. The DAT-SPECT examination was performed 6 months after disease onset in one of these patients who manifested rapidly developing cognitive decline mimicking Creutzfeldt-Jakob disease. DAT-SPECT was also performed 9 years after disease onset in another patient who manifested the conventional features of GSS involving ataxia and dementia in the initial phase but showed akinetic mutism at the examination time. Another patient examined 2 years after disease onset who predominantly manifested ataxia showed marginally abnormal SBR values. An autopsy case showed moderate neuronal loss in the substantia nigra, and the degree of neuronal loss was similar in most other parts of the brain. CONCLUSION: Nigrostriatal system involvement may occur in patients with GSS associated with the PRNP-P102L mutation, even though parkinsonism is not the predominant feature.
Asunto(s)
Cuerpo Estriado , Enfermedad de Gerstmann-Straussler-Scheinker , Mutación , Proteínas Priónicas , Priones , Sustancia Negra , Tomografía Computarizada de Emisión de Fotón Único , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/patología , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Enfermedad de Gerstmann-Straussler-Scheinker/patología , Enfermedad de Gerstmann-Straussler-Scheinker/diagnóstico por imagen , Nortropanos , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Priones/genética , Priones/metabolismo , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Sustancia Negra/metabolismoRESUMEN
The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants1-3. Despite decades of study, the structure, substrate binding, conformational transitions and drug-binding poses of human dopamine transporter remain unknown. Here we report structures of the human dopamine transporter in its apo state, and in complex with the substrate dopamine, the attention deficit hyperactivity disorder drug methylphenidate, and the dopamine-uptake inhibitors GBR12909 and benztropine. The dopamine-bound structure in the occluded state precisely illustrates the binding position of dopamine and associated ions. The structures bound to drugs are captured in outward-facing or inward-facing states, illuminating distinct binding modes and conformational transitions during substrate transport. Unlike the outward-facing state, which is stabilized by cocaine, GBR12909 and benztropine stabilize the dopamine transporter in the inward-facing state, revealing previously unseen drug-binding poses and providing insights into how they counteract the effects of cocaine. This study establishes a framework for understanding the functioning of the human dopamine transporter and developing therapeutic interventions for dopamine transporter-related disorders and cocaine addiction.
Asunto(s)
Benzotropina , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina , Dopamina , Humanos , Apoproteínas/metabolismo , Apoproteínas/química , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Benzotropina/metabolismo , Benzotropina/farmacología , Sitios de Unión , Cocaína/farmacología , Cocaína/metabolismo , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/química , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Metilfenidato/metabolismo , Metilfenidato/farmacología , Modelos Moleculares , Piperazinas/metabolismo , Piperazinas/farmacología , Unión Proteica , Conformación ProteicaRESUMEN
The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement1. Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn2+ are without a high-resolution structural context. Here we determine the structure of hDAT in a tripartite complex with the competitive inhibitor and cocaine analogue, (-)-2-ß-carbomethoxy-3-ß-(4-fluorophenyl)tropane2 (ß-CFT), the non-competitive inhibitor MRS72923 and Zn2+ (ref. 4). We show how ß-CFT occupies the central site, approximately halfway across the membrane, stabilizing the transporter in an outward-open conformation. MRS7292 binds to a structurally uncharacterized allosteric site, adjacent to the extracellular vestibule, sequestered underneath the extracellular loop 4 (EL4) and adjacent to transmembrane helix 1b (TM1b), acting as a wedge, precluding movement of TM1b and closure of the extracellular gate. A Zn2+ ion further stabilizes the outward-facing conformation by coupling EL4 to EL2, TM7 and TM8, thus providing specific insights into how Zn2+ restrains the movement of EL4 relative to EL2 and inhibits transport activity.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Inhibidores de Captación de Dopamina , Humanos , Sitio Alostérico/efectos de los fármacos , Cocaína/análogos & derivados , Cocaína/química , Cocaína/metabolismo , Cocaína/farmacología , Microscopía por Crioelectrón , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/química , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/ultraestructura , Inhibidores de Captación de Dopamina/química , Inhibidores de Captación de Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Modelos Moleculares , Movimiento/efectos de los fármacos , Conformación Proteica/efectos de los fármacos , Zinc/metabolismo , Zinc/química , Zinc/farmacologíaRESUMEN
Social behavior is sexually dimorphic, which is regulated by gonadal hormones in the brain. Our recent study found that exposure to low doses of bisphenol-A (BPA) during adolescence, permanently alters social behavior in adult male mice, but the underlying mechanisms remain unclear. Using adolescent gonadectomy (GDX) male mice with testosterone propionate (TP, 0.5 mg/kg) supplement (TP-GDX), this study showed that BPA antagonized promoting effects of TP on social interaction, sexual behavior, and aggression in GDX mice. BPA eliminated the reversal effects of TP on GDX-induced decrease in the number of immunoreactive to arginine vasopressin (AVP-ir) neurons in the medial amygdala (MeA) and the levels of AVP receptor 1a (V1aR) in the MeA and the nucleus accumbens (NAc). In addition, BPA removed down-regulation in the levels of dopamine (DA) transporter (DAT) and DA receptor 1 (DR1) in the NAc of TP-GDX mice. BPA exposure reduced testosterone (T) levels in the brain and serum and the expression of androgen receptor (AR) protein in the amygdala and striatum of sham-operated and TP-GDX males. These results suggest that adolescent exposure to BPA inhibits regulation of androgen in AVP and DA systems of the brain regions associated with social behavior, and thus alters social behaviors of adult male mice.
Asunto(s)
Compuestos de Bencidrilo , Fenoles , Receptores Androgénicos , Conducta Social , Animales , Masculino , Fenoles/toxicidad , Compuestos de Bencidrilo/toxicidad , Compuestos de Bencidrilo/farmacología , Ratones , Receptores Androgénicos/metabolismo , Receptores Androgénicos/efectos de los fármacos , Testosterona/sangre , Testosterona/metabolismo , Receptores de Dopamina D1/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Agresión/efectos de los fármacos , Conducta Sexual Animal/efectos de los fármacos , Andrógenos/farmacología , Propionato de Testosterona/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Arginina Vasopresina/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismoAsunto(s)
Conducta Adictiva , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Terapia Molecular Dirigida , Trastornos Relacionados con Sustancias , Humanos , Conducta Adictiva/tratamiento farmacológico , Conducta Adictiva/metabolismo , Cocaína/metabolismo , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/química , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Terapia Molecular Dirigida/tendencias , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Trastornos Relacionados con Sustancias/metabolismoRESUMEN
The dopamine transporter (DAT) is crucial for regulating dopamine signalling and is the prime mediator for the rewarding and addictive effects of cocaine1. As part of the neurotransmitter sodium symporter family, DAT uses the Na+ gradient across cell membranes to transport dopamine against its chemical gradient2. The transport mechanism involves both intra- and extracellular gates that control substrate access to a central site. However, the molecular intricacies of this process and the inhibitory mechanism of cocaine have remained unclear. Here, we present the molecular structure of human DAT in complex with cocaine at a resolution of 2.66 Å. Our findings reveal that DAT adopts the expected LeuT-fold, posing in an outward-open conformation with cocaine bound at the central (S1) site. Notably, while an Na+ occupies the second Na+ site (Na2), the Na1 site seems to be vacant, with the side chain of Asn82 occupying the presumed Na+ space. This structural insight elucidates the mechanism for the cocaine inhibition of human DAT and deepens our understanding of neurotransmitter transport. By shedding light on the molecular underpinnings of how cocaine acts, our study lays a foundation for the development of targeted medications to combat addiction.
Asunto(s)
Cocaína , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Humanos , Sitios de Unión , Cocaína/metabolismo , Cocaína/química , Cocaína/farmacología , Microscopía por Crioelectrón , Dopamina/metabolismo , Dopamina/química , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/química , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/ultraestructura , Modelos Moleculares , Neurotransmisores/metabolismo , Unión Proteica , Conformación Proteica/efectos de los fármacos , Sodio/química , Sodio/metabolismoRESUMEN
The core of clinic treatment of Parkinson's disease (PD) is to enhance dopamine (DA) signaling within the brain. The regulation of dopamine transporter (DAT) is integral to this process. This study aims to explore the regulatory mechanism of glial cell line-derived neurotrophic factor (GDNF) on DAT, thereby gaining a profound understanding its potential value in treating PD. In this study, we investigated the effects of GDNF on both cellular and mouse models of PD, including the glycosylation and membrane transport of DAT detected by immunofluorescence and immunoblotting, DA signal measured by neurotransmitter fiber imaging technology, Golgi morphology observed by electron microscopic, as well as cognitive ability assessed by behavior tests. This study revealed that in animal trials, MPTP-induced Parkinson's Disease (PD) mice exhibited a marked decline in cognitive function. Utilizing ELISA and neurotransmitter fiber imaging techniques, we observed a decrease in dopamine levels and a significant reduction in the intensity of dopamine signal release in the Prefrontal Cortex (PFC) of PD mice induced by MPTP. Intriguingly, these alterations were reversed by Glial Cell Line-Derived Neurotrophic Factor (GDNF). In cellular experiments, following MPP + intervention, there was a decrease in Gly-DAT modification in both the cell membrane and cytoplasm, coupled with an increase in Nongly-DAT expression and aggregation of DAT within the cytoplasm. Conversely, GDNF augmented DAT glycosylation and facilitated its membrane transport in damaged dopaminergic neurons, concurrently reversing the effects of GRASP65 depletion and Golgi fragmentation, thereby reducing the accumulation of DAT in the Golgi apparatus. Furthermore, overexpression of GRASP65 enhanced DAT transport in PD cells and mice, while suppression of GRASP65 attenuated the efficacy of GDNF on DAT. Additionally, GDNF potentiated the reutilization of neurotransmitters by the PFC presynaptic membrane, boosting the effective release of dopamine following a single electrical stimulation, ultimately ameliorating the cognitive impairments in PD mice.Therefore, we propose that GDNF enhances the glycosylation and membrane trafficking of DAT by facilitating the re-aggregation of the Golgi apparatus, thereby amplifying the utilization of DA signals. This ultimately leads to the improvement of cognitive abilities in PD mouse models. Our study illuminates, from a novel angle, the beneficial role of GDNF in augmenting DA utilization and cognitive function in PD, providing fresh insights into its therapeutic potential.
Asunto(s)
Cognición , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Dopamina , Factor Neurotrófico Derivado de la Línea Celular Glial , Animales , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Glicosilación , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Ratones , Cognición/efectos de los fármacos , Dopamina/metabolismo , Masculino , Enfermedad de Parkinson/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Membrana Celular/metabolismo , Corteza Prefrontal/metabolismoRESUMEN
BACKGROUND: Sphingolipid dysregulation in Parkinson's disease (PD) may affect the release and uptake of striatal dopamine. However, the longitudinal relationship between sphingolipids, striatal dopaminergic degeneration, and clinical correlates in idiopathic PD (iPD) remain unclear. OBJECTIVE: To investigate the relationship between plasma sphingolipids, striatal dopamine transporter specific binding ratio (DAT-SBR) and clinical symptoms in iPD. METHODS: We included 283 iPD patients and 121 healthy controls (HC) from the Parkinson's Progression Markers Initiative (PPMI), utilizing available data on plasma sphingolipids (sphingomyelin [SM] and ceramide [CER]), striatal DAT-SBR and clinical assessments. Linear mixed models and mediation analyses were used to examine the relationship between sphingolipids, DAT-SBR, and clinical progression in iPD. RESULTS: Lower baseline SM levels were significantly associated with a faster decline in DAT-SBR in both the caudate (p = 0.015) and putamen (p = 0.002), with the putamen association remaining significant after Bonferroni correction (p = 0.015). No significant association was found for CER. Patients in the lowest quartile of baseline SM showed faster progression in MDS-UPDRS I (p = 0.013) and II (p = 0.011), while those in the lowest quartile of baseline CER showed faster progression in MDS-UPDRS II (p = 0.013) and III (p = 0.033). The progression rate of caudate DAT-SBR partially mediated the relationships between SM and progression in MDS-UPDRS I and II (p < 0.01). CONCLUSION: Sphingolipids are associated with worse dopaminergic degeneration and potentially linked to faster progression in iPD, holding the promise for identifying individuals with faster progression in iPD.
Asunto(s)
Progresión de la Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Enfermedad de Parkinson , Esfingolípidos , Humanos , Enfermedad de Parkinson/sangre , Masculino , Femenino , Anciano , Persona de Mediana Edad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Esfingolípidos/sangre , Esfingomielinas/sangre , Ceramidas/sangre , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Dopamina/sangre , Dopamina/metabolismoRESUMEN
We propose strongly unrealistic data augmentation to improve the robustness of convolutional neural networks (CNNs) for automatic classification of dopamine transporter SPECT against the variability between sites and between cameras. Methods: A CNN was trained on a homogeneous dataset comprising 1,100 123I-labeled 2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)nortropane SPECT images using strongly unrealistic data augmentation based on gaussian blurring and additive noise. Strongly unrealistic data augmentation was compared with no augmentation and intensity-based nnU-Net augmentation on 2 independent datasets with lower (n = 645) and considerably higher (n = 640) spatial resolution. Results: The CNN trained with strongly unrealistic augmentation achieved an overall accuracy of 0.989 (95% CI, 0.978-0.996) and 0.975 (95% CI, 0.960-0.986) in the independent test datasets, which was better than that without (0.960, 95% CI, 0.942-0.974; 0.953, 95% CI, 0.934-0.968) and with nnU-Net augmentation (0.972, 95% CI, 0.956-0.983; 0.950, 95% CI, 0.930-0.966) (all McNemar P < 0.001). Conclusion: Strongly unrealistic data augmentation results in better generalization of CNN-based classification of 123I-labeled 2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)nortropane SPECT images to unseen acquisition settings. We hypothesize that this can be transferred to other nuclear imaging applications.
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Aprendizaje Profundo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Procesamiento de Imagen Asistido por Computador , Tomografía Computarizada de Emisión de Fotón Único , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
OBJECTIVE: Dysphagia in multiple system atrophy (MSA) is life-threatening and is caused by parkinsonism with cerebellar ataxia as a contributing factor. The present study investigated the relationship between dysphagia severity in MSA and the specific binding ratio (SBR) on dopamine transporter (DaT) SPECT using the Hyodo score, a qualitative scale for use with fiberoptic endoscopic evaluation of swallowing (FEES). METHODS: Hyodo score's ability to predict aspiration during a FEES examination of 88 patients with MSA was first tested. Then the clinical characteristics, Hyodo score, and SBR of patients with either predominant parkinsonism (MSA-P; n = 11) or cerebellar ataxia (MSA-C; n = 25) who underwent FEES and DaT SPECT simultaneously were compared. RESULTS: Logistic regression demonstrated that the Hyodo score was a significant predictive factor of aspiration (p = 0.003). The MSA-P group had a significantly higher Hyodo score (p = 0.026) and lower SBR (p = 0.011) than the MSA-C group while neither group demonstrated any significant difference in disease duration at the FEES examination. Linear regression demonstrated a significant, inverse correlation between the Hyodo score and SBR in the MSA-P (p = 0.044; r = -0.616) and MSA-C (p = 0.044; r = -0.406) groups. When the effect of SBR was removed by analysis of covariance, no significant difference in the Hyodo score remained between the groups. CONCLUSIONS: Our results suggested an association between presynaptic changes in nigrostriatal dopaminergic neurons and dysphagia severity in MSA which largely contributes to the difference in dysphagia severity between MSA-P and MSA-C.
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Trastornos de Deglución , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Atrofia de Múltiples Sistemas , Índice de Severidad de la Enfermedad , Tomografía Computarizada de Emisión de Fotón Único , Humanos , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/metabolismo , Masculino , Femenino , Trastornos de Deglución/diagnóstico por imagen , Trastornos de Deglución/etiología , Anciano , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Persona de Mediana EdadRESUMEN
INTRODUCTION: DAT-SPECT imaging is approved as a diagnostic tool for the evaluation of suspected Parkinsonian syndromes, but the FDA-approved package insert lists 16 potential drugs that may interfere with the image obtained. The clinical impact of these drugs on imaging results has not been established. This study aimed to determine the accuracy of DAT-SPECT imaging in assessing presynaptic dopaminergic denervation in the setting of these drugs. METHODS: This is a retrospective chart review of patients at a single center who underwent DAT-SPECT imaging while taking "contraindicated" drugs between December 2012 and December 2022. RESULTS: A total of 1,224 charts were screened, and 153 (12.5%) charts met the inclusion criteria. Bupropion (32%, n = 49) and sertraline (26%, n = 40) were the most common contraindicated drugs. The false-positive rate was 9.2%. CONCLUSION: This retrospective analysis supports the concern that certain drugs may interfere with DAT-SPECT imaging results, leading to potential false positives. This has implications for how clinicians interpret DAT-SPECT imaging in patients taking these medications and whether they should advise patients to stop these medications before a scan is performed.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Interacciones Farmacológicas , Tomografía Computarizada de Emisión de Fotón Único , Humanos , Estudios Retrospectivos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Anciano , Trastornos del Movimiento/diagnóstico por imagenRESUMEN
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.
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Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Trastornos Parkinsonianos , Probenecid , Estimulación Magnética Transcraneal , Animales , Estimulación Magnética Transcraneal/métodos , Ratones , Masculino , Probenecid/farmacología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/terapia , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Motora/metabolismo , Corteza Motora/fisiopatología , Neuronas Dopaminérgicas/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Interleucina-1beta/metabolismo , Sustancia Negra/metabolismo , Cuerpo Estriado/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Intoxicación por MPTP/terapia , Intoxicación por MPTP/prevención & control , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/fisiopatología , Actividad Motora/fisiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacologíaRESUMEN
Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.