RESUMEN
Among the symptoms of Parkinson's disease (PD), apathy comprises a set of behavioral, affective, and cognitive features that can be classified into several subtypes. However, the pathophysiology and brain regions that are involved in these different apathy subtypes are still poorly characterized. We examined which subtype of apathy is elicited in a mouse model of PD with 6-hydroxydopamine (6-OHDA) lesions and the behavioral symptoms that are exhibited. Male C57/BL6J mice were allocated to sham (n = 8) and 6-OHDA (n = 13) groups and locally injected with saline or 4 µg 6-OHDA bilaterally in the dorsal striatum. We then conducted motor performance tests and apathy-related behavioral experiments. We then pathologically evaluated tyrosine hydroxylase (TH) immunostaining. The 6-OHDA group exhibited significant impairments in motor function. In the behavioral tests of apathy, significant differences were observed between the sham and 6-OHDA groups in the hole-board test and novelty-suppressed feeding test. The 6-OHDA group exhibited impairments in inanimate novel object preference, whereas social preference was maintained in the three-chamber test. The number of TH+ pixels in the caudate putamen and substantia nigra compacta was significantly reduced in the 6-OHDA group. The present mouse model of PD predominantly showed dorsal striatum dopaminergic neuronal loss and a decrease in novelty seeking as a symptom that is related to the cognitive apathy component.
Asunto(s)
Apatía , Conducta Animal , Cuerpo Estriado , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Oxidopamina , Enfermedad de Parkinson , Animales , Oxidopamina/farmacología , Oxidopamina/efectos adversos , Apatía/efectos de los fármacos , Masculino , Ratones , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Cuerpo Estriado/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , Actividad Motora/efectos de los fármacosRESUMEN
Dopamine-deficient (DD) mice exhibit psychomotor hyperactivity that might be related to a decrease in muscarinic signaling. In the present study, muscarinic acetylcholine receptor M2 (CHRM2) density decreased in the cortex in DD mice. This is significant because cortical CHRM2 acts as an autoreceptor; therefore, changes in CHRM2 levels could alter acetylcholine in DD mice. We also found that the CHRM1/CHRM4 agonist xanomeline and CHRM2 agonist arecaidine propargyl ester tosylate inhibited hyperactivity in DD mice, suggesting that postsynaptic CHRM1 and CHRM2 and presynaptic CHRM2 may be involved in hyperactivity in DD mice.
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Dopamina , Agitación Psicomotora , Ratones , Animales , Acetilcolina/farmacología , Ésteres , Transducción de SeñalRESUMEN
Some diseases that are associated with dopamine deficiency are accompanied by psychiatric symptoms, including Parkinson's disease. However, the mechanism by which this occurs has not been clarified. Previous studies found that dopamine-deficient (DD) mice exhibited hyperactivity in a novel environment. This hyperactivity is improved by clozapine and donepezil, which are used to treat psychiatric symptoms associated with dopamine deficiency (PSDD). We considered that DD mice could be used to study PSDD. In the present study, we sought to identify the pharmacological mechanism of PSDD. We conducted locomotor activity tests by administering quetiapine and drugs that have specific actions on serotonin (5-hydroxytryptamine [5-HT]) receptors and muscarinic receptors. Changes in neuronal activity that were induced by drug administration in DD mice were evaluated by examining Fos immunoreactivity. Quetiapine suppressed hyperactivity in DD mice while the 5-HT1A receptor antagonist WAY100635 inhibited this effect. The number of Fos-positive neurons in the median raphe nucleus increased in DD mice that exhibited hyperactivity and was decreased by treatment with quetiapine and 5-HT1A receptor agonists. In conclusion, hyperactivity in DD mice was ameliorated by quetiapine, likely through 5-HT1A receptor activation. These findings suggest that 5-HT1A receptors may play a role in PSDD, and 5-HT1A receptor-targeting drugs may help improve PSDD.
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Antipsicóticos , Dopamina , Fumarato de Quetiapina , Receptor de Serotonina 5-HT1A , Agonistas del Receptor de Serotonina 5-HT1 , Animales , Antipsicóticos/farmacología , Dopamina/deficiencia , Dopamina/metabolismo , Ratones , Fumarato de Quetiapina/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Antagonistas de la Serotonina/farmacologíaRESUMEN
Despite the established roles of the dopaminergic system in promoting arousal, the effects of loss of dopamine on the patterns of sleep and wakefulness remain elusive. Here, we examined the sleep architecture of dopamine-deficient (DD) mice, which were previously developed by global knockout of tyrosine hydroxylase and its specific rescue in noradrenergic and adrenergic neurons. We found that DD mice have reduced time spent in wakefulness. Unexpectedly, DD mice also exhibited a marked reduction in the time spent in rapid eye movement (REM) sleep. The electroencephalogram power spectrum of all vigilance states in DD mice were also affected. These results support the current understanding of the critical roles of the dopaminergic system in maintaining wakefulness and also implicate its previously unknown effects on REM sleep.
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Sueño REM , Vigilia , Animales , Dopamina , Electroencefalografía , Ratones , Sueño/fisiología , Sueño REM/fisiología , Vigilia/fisiologíaRESUMEN
Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson's disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of ß-synuclein (ßS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer's disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid ß and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.
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Enfermedad de Gaucher/metabolismo , Enfermedad de Gaucher/terapia , alfa-Sinucleína/metabolismo , Amiloide/metabolismo , Autofagia , Encéfalo/metabolismo , Enfermedad de Gaucher/genética , Glucosilceramidasa/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisosomas/metabolismo , Modelos Biológicos , Mutación , Proteína Niemann-Pick C1 , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/terapia , Especies Reactivas de Oxígeno , Riesgo , Factores de Riesgo , Resultado del Tratamiento , Sinucleína beta/metabolismoRESUMEN
Dopamine is involved in many important brain functions, including voluntary motor movement. Dysfunction of the dopaminergic system can induce motor impairments, including Parkinson's disease. We previously found that dopamine-deficient (DD) mice became hyperactive in a novel environment 72 h after the last injection of L-3,4-dihydroxyphenylalanine (L-DOPA) when dopamine was almost completely depleted. In the present study, we investigated neuronal activity in hippocampal subregions during hyperactivity by measuring Fos expression levels using immunohistochemistry. Dopamine-deficient mice were maintained on daily intraperitoneal injections of 50 mg/kg L-DOPA. Seventy-two hours after the last L-DOPA injection, DD mice were exposed to a novel environment for 1, 2, or 4 h, and then brains were collected. In wildtype mice, the number of Fos-immunopositive neurons significantly increased in the hippocampal CA1 region after 1 h of exposure to the novel environment and then decreased. In DD mice, the number of Fos-immunopositive neurons gradually increased and then significantly increased after 4 h of exposure to the novel environment. The number of Fos-immunopositive neurons also significantly increased in the CA3 region and dentate gyrus in DD mice after 4 h of exposure to the novel environment. These results indicate that the delayed and prolonged excitation of hippocampal neurons in the CA1, CA3, and dentate gyrus that is caused by dopamine depletion might be involved in hyperactivity in DD mice.
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Dopamina/deficiencia , Conducta Exploratoria , Hipocampo/fisiología , Locomoción , Neuronas/fisiología , Animales , Dopamina/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer's disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of ß-synuclein (ßS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which ßS mutations promote DLB pathogenesis remain elusive. To further clarify such mechanisms, we investigated transgenic (Tg) mice expressing P123H ßS, which develop progressive neurodegeneration in the form of axonal swelling and non-motor behaviors, such as memory dysfunction and depression, which are more prominent than motor deficits. Furthermore, cross-breeding of P123H ßS Tg mice with αS Tg mice worsened the neurodegenerative phenotype presumably through the pathological cross-seeding of P123H ßS with αS. Collectively, we predict that ßS misfolding due to gene mutations might be pathogenic. In this paper, we will discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB based on our previous papers regarding the P123H ßS Tg mice. Given that stimulation of αS evolvability by P123H ßS may underlie neuropathology in our mouse model, more radical disease-modifying therapy might be derived from the evolvability mechanism. Additionally, provided that altered ßS were involved in the pathogenesis of sporadic DLB, the P123H ßS Tg mice could be used for investigating the mechanism and therapy of DLB.
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Proteínas Amiloidogénicas/genética , Proteínas Amiloidogénicas/metabolismo , Enfermedad por Cuerpos de Lewy/etiología , Enfermedad por Cuerpos de Lewy/metabolismo , Sinucleína beta/genética , Sinucleína beta/metabolismo , Alelos , Sustitución de Aminoácidos , Animales , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Expresión Génica , Humanos , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/terapia , Ratones , Ratones Transgénicos , MutaciónRESUMEN
Introduction: Biomarkers for Parkinson's disease and Alzheimer's disease are essential, not only for disease detection, but also provide insight into potential disease relationships leading to better detection and therapy. As metabolic disease is known to increase neurodegeneration risk, such mechanisms may reveal such novel targets for PD and AD. Moreover, metabolic disease, including insulin resistance, offer novel biomarker and therapeutic targets for neurodegeneration, including glucagon-like-peptide-1, dipeptidyl peptidase-4 and adiponectin. Areas covered: The authors reviewed PubMed-listed research articles, including ours, on a number of putative PD, AD and neurodegenerative disease targets of interest, focusing on the relevance of metabolic syndrome and insulin resistance mechanisms, especially type II diabetes, to PD and AD. We highlighted various issues surrounding the current state of knowledge and propose avenues for future development. Expert opinion: Biomarkers for PD and AD are indispensable for disease diagnosis, prognostication and tracking disease severity, especially for clinical therapy trials. Although no validated PD biomarkers exist, their potential utility has generated tremendous interest. Combining insulin-resistance biomarkers with other core biomarkers or using them to predict non-motor symptoms of PD may be clinically useful. Collectively, although still unclear, potential biomarkers and therapies can aid in shedding new light on novel aspects of both PD and AD.
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Biomarcadores , Demencia/diagnóstico , Síndrome Metabólico/diagnóstico , Enfermedad de Parkinson/diagnóstico , HumanosRESUMEN
A common notion is that essentially all addictive drugs, including opioids, activate dopaminergic pathways in the brain reward system, and the inappropriate use of such drugs induces drug dependence. However, an opioid reward response is reportedly still observed in several models of dopamine depletion, including in animals that are treated with dopamine blockers, animals that are subjected to dopaminergic neuron lesions, and dopamine-deficient mice. The intracranial self-stimulation response is enhanced by stimulants but reduced by morphine. These findings suggest that dopaminergic neurotransmission may not always be required for opioid reward responses. Previous findings also indicate the possibility that dopamine-independent opioid reward may be observed in opioid-naive states but not in opioid-dependent states. Therefore, a history of opioid use should be considered when evaluating the dopamine dependency of opioid reward.
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Analgésicos Opioides/administración & dosificación , Encéfalo/metabolismo , Dopamina/metabolismo , Red Nerviosa/metabolismo , Recompensa , Trastornos Relacionados con Sustancias/metabolismo , Animales , Encéfalo/efectos de los fármacos , Ratones , Red Nerviosa/efectos de los fármacosRESUMEN
AIM: We previously generated transgenic (Tg) mice that expressed P123H ß-synuclein (ßS), a dementia with Lewy body-linked mutant ßS. Notably, these mice recapitulated neurodegenerative features of Lewy body disease, reflected by motor dysfunction, greater protein aggregation, and memory impairment. Since recent studies suggested that non-motor symptoms, such as depression, might be manifested in the prodromal stage of Lewy body disease, the main objective of the present study was to investigate the early expression of behavior in P123H ßS Tg mice. METHODS: Nest building, locomotor activity, and depressive-like behavior were assessed using 6- to 10-month-old male and female P123H ßS Tg and wildtype mice. KEY RESULTS: P123H ßS Tg mice exhibited hyperlocomotor activity in a novel environment, a decrease in mobility time in the tail suspension test, and impairments in nest building. CONCLUSIONS: Importantly, these non-motor behaviors were manifested before the onset of motor dysfunction, suggesting that P123H ßS Tg mice could be a valid model for investigating the early phase of Lewy body disease.
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Depresión/genética , Enfermedad por Cuerpos de Lewy/genética , Mutación Missense , Sinucleína beta/genética , Animales , Depresión/fisiopatología , Femenino , Enfermedad por Cuerpos de Lewy/fisiopatología , Locomoción , Masculino , Ratones , Comportamiento de NidificaciónRESUMEN
AIM: Maturation abnormalities of the brain cells have been suggested in several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorders, and epilepsy. In this study, we examined the expression patterns of neuronal maturation markers in the brain of a mouse model of dementia with Lewy body-linked mutant ß-synuclein (ßS), especially in the hippocampus, to explore whether such brain abnormalities occur in neurodegenerative disorders as well. METHODS: Quantitative PCR (qPCR) and immunohistochemical analyses were performed using the hippocampus of 14-month-old P123H ßS transgenic (Tg) mice to evaluate the expression of molecular markers for maturation of dentate granule cells. RESULTS: Based on qPCR results, expression of Tdo2 and Dsp (markers of mature granule cells) was decreased and that of Drd1a (a marker of immature granule cells) was increased in the hippocampus of P123H ßS Tg mice compared to that in wild-type controls. Immunohistochemical analysis revealed decreased expression of mature granule cell markers Calb1 and Gria1, along with increased expression of the microglial marker Iba1, in the hippocampal dentate gyrus region of P123H ßS Tg mice. P123H ßS Tg mice exhibited immature-like neuronal molecular expression patterns and microgliosis in the hippocampus. Pseudo-immaturity of dentate granule cells, associated with neuroinflammation, may be a shared endophenotype in the brains of at least a subgroup of patients with neuropsychiatric disorders and neurodegenerative diseases.
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Demencia/genética , Hipocampo/metabolismo , Hipocampo/patología , Cuerpos de Lewy/genética , Cuerpos de Lewy/patología , Mutación/genética , Sinucleína beta/genética , Animales , Giro Dentado/metabolismo , Giro Dentado/patología , Modelos Animales de Enfermedad , Ratones Transgénicos , Fenotipo , Sinucleína beta/metabolismoRESUMEN
Lewy body diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as α-synuclein (αS) and amyloid-ß (Aß) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.
RESUMEN
Dopamine is important for motor control and involved in the regulation of circadian rhythm. We previously found that dopamine-deficient (DD) mice became hyperactive in a novel environment 72 h after the last injection of L-3,4-dihydroxyphenylalanine (L-DOPA) when dopamine was almost completely depleted. DD mice did not initially exhibit hyperactivity in their home cages, but the animals exhibited hyperactivity several hours after the last L-DOPA injection. The regulation of motor activity in a novel environment and in home cages may be different. A previous study reported that DD mice became active again approximately 24 h after the last L-DOPA injection. One speculation was that light/dark phase-dependent spontaneous activity might be maintained despite dopamine deficiency. The present study investigated whether spontaneous home cage activity is maintained in DD mice 24-43 h and 72-91 h after the last L-DOPA injection. Spontaneous activity was almost completely suppressed during the light phase of the light/dark cycle in DD mice 24 and 72 h after the last L-DOPA injection. After the dark phase began, DD mice became active 24 and 72 h after the last L-DOPA injection. DD mice exhibited a similar amount of locomotor activity as wildtype mice 24 h after the last L-DOPA injection. Although DD mice presented a decrease in activity 72 h after the last L-DOPA injection, they maintained dark phase-stimulated locomotor activation. Despite low levels of dopamine in DD mice, they exhibited feeding behavior that was similar to wildtype mice. Although grooming and rearing behavior significantly decreased, DD mice retained their ability to perform these activities. Haloperidol treatment significantly suppressed all of these behaviors in wildtype mice but not in DD mice. These results indicate that DD mice maintain some aspects of light/dark phase-dependent spontaneous activity despite dopamine depletion, suggesting that compensatory dopamine-independent mechanisms might play a role in the DD mouse phenotype.
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Ritmo Circadiano/fisiología , Dopamina/deficiencia , Luz , Animales , Conducta Alimentaria/efectos de los fármacos , Aseo Animal/efectos de los fármacos , Haloperidol/farmacología , Locomoción/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
PURPOSE: To investigate the diagnostic capability of ultra-low-dose CT (ULDCT) with full iterative reconstruction (f-IR) for lung cancer screening. MATERIALS AND METHODS: All underwent ULDCT and/or low-dose CT (LD-CT) on a 320-detector scanner. ULDCT images were reconstructed with f-IR. We qualitatively and quantitatively studied 95 nodules in 69 subjects. Two radiologists classified the nodules on ULDCT images as solid-, part-solid-, and pure ground-glass (PGG) and recorded their mean size. Their findings were compared with the reference standard. The observer performance study included 7 other radiologists and 35 subjects with- and 15 without nodules. The results were analyzed by AFROC analysis. RESULTS: In the qualitative study, the kappa values between observers 1 and 2, respectively, and the reference standard were 0.70 and 0.83; the intra-class correlation coefficients for the nodule diameter between the reference standard and their measurements were 0.84 and 0.90. The 95% confidence interval (CI) for the area under the curve (AUC) difference for nodule detection on LDCT and ULDCT was -0.03 to 0.07. The 95% CI crossed the 0 difference in the AUC but not the pre-defined non-inferiority margin of -0.08. CONCLUSION: The diagnostic ability of ULDCT using f-IR is comparable to LDCT.
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Neoplasias Pulmonares/diagnóstico por imagen , Anciano , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dosis de Radiación , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
RATIONALE AND OBJECTIVES: This study aimed to evaluate the effects of iterative reconstruction (IR) algorithms on computer-assisted detection (CAD) software for lung nodules in ultra-low-dose computed tomography (ULD-CT) for lung cancer screening. MATERIALS AND METHODS: We selected 85 subjects who underwent both a low-dose CT (LD-CT) scan and an additional ULD-CT scan in our lung cancer screening program for high-risk populations. The LD-CT scans were reconstructed with filtered back projection (FBP; LD-FBP). The ULD-CT scans were reconstructed with FBP (ULD-FBP), adaptive iterative dose reduction 3D (AIDR 3D; ULD-AIDR 3D), and forward projected model-based IR solution (FIRST; ULD-FIRST). CAD software for lung nodules was applied to each image dataset, and the performance of the CAD software was compared among the different IR algorithms. RESULTS: The mean volume CT dose indexes were 3.02 mGy (LD-CT) and 0.30 mGy (ULD-CT). For overall nodules, the sensitivities of CAD software at 3.0 false positives per case were 78.7% (LD-FBP), 9.3% (ULD-FBP), 69.4% (ULD-AIDR 3D), and 77.8% (ULD-FIRST). Statistical analysis showed that the sensitivities of ULD-AIDR 3D and ULD-FIRST were significantly higher than that of ULD-FBP (P < .001). CONCLUSIONS: The performance of CAD software in ULD-CT was improved by using IR algorithms. In particular, the performance of CAD in ULD-FIRST was almost equivalent to that in LD-FBP.
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Algoritmos , Neoplasias Pulmonares/diagnóstico por imagen , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Programas Informáticos , Anciano , Tomografía Computarizada de Haz Cónico , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dosis de Radiación , Interpretación de Imagen Radiográfica Asistida por Computador/métodos , Cintigrafía , Tomografía Computarizada por Rayos X/métodosRESUMEN
Dopaminergic systems have been known to be involved in the regulation of locomotor activity and development of psychosis. However, the observations that some Parkinson's disease patients can move effectively under appropriate conditions despite low dopamine levels (eg, kinesia paradoxia) and that several psychotic symptoms are typical antipsychotic resistant and atypical antipsychotic sensitive indicate that other systems beyond the dopaminergic system may also affect locomotor activity and psychosis. The present study showed that dopamine-deficient (DD) mice, which had received daily L-DOPA injections, could move effectively and even be hyperactive 72 h after the last L-DOPA injection when dopamine was almost completely depleted. Such hyperactivity was ameliorated by clozapine but not haloperidol or ziprasidone. Among multiple actions of clozapine, muscarinic acetylcholine (ACh) activation markedly reduced locomotor activity in DD mice. Furthermore, the expression of choline acetyltransferase, an ACh synthase, was reduced and extracellular ACh levels were significantly reduced in DD mice. These results suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in motor control, including hyperactivity and psychosis. The present findings provide additional evidence that the cholinergic system may be targeted for the treatment of Parkinson's disease and psychosis.
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Acetilcolina/metabolismo , Acatisia Inducida por Medicamentos/metabolismo , Dopaminérgicos/toxicidad , Dopamina/deficiencia , Levodopa/toxicidad , Agitación Psicomotora/metabolismo , Acatisia Inducida por Medicamentos/tratamiento farmacológico , Animales , Antidiscinéticos/farmacología , Antipsicóticos/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Colina O-Acetiltransferasa/metabolismo , Clozapina/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Haloperidol/farmacología , Locomoción/efectos de los fármacos , Locomoción/fisiología , Ratones Endogámicos C57BL , Piperazinas/farmacología , Agitación Psicomotora/tratamiento farmacológico , Tiazoles/farmacologíaRESUMEN
OBJECTIVE: Growing evidence suggests that neurodegenerative diseases are associated with metabolic disorders, but the mechanisms are still unclear. Better comprehension of this issue might provide a new strategy for treatment of neurodegenerative diseases. We investigated possible roles of adiponectin (APN), the anti-diabetes protein, in the pathogenesis of α-synucleinopathies. METHODS: Using biochemical and histological methods, we investigated autopsy brain of α-synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and analyzed the effects of APN in cellular and in mouse models of α-synucleinopathies. RESULTS: We observed that APN is localized in Lewy bodies derived from α-synucleinopathies such as Parkinson's disease and dementia with Lewy bodies. In neuronal cells expressing α-synuclein (αS), aggregation of αS was suppressed by treatment with recombinant APN in an AdipoRI-AMP kinase pathway-dependent manner. Concomitantly, phosphorylation and release of αS were significantly decreased by APN, suggesting that APN may be antineurodegenerative. In transgenic mice expressing αS, both histopathology and movement disorder were significantly improved by intranasal treatment with globular APN when the treatment was initiated in the early stage of the disease. In a mouse model, reduced levels of guanosine- and inosine- monophosphates, both of which are potential stimulators of aggregation of αS, might partly contribute to suppression of aggregation of αS by APN. INTERPRETATION: Taken together, APN may suppress neurodegeneration through modification of the metabolic pathway, and could possess a therapeutic potential against α-synucleinopathies.
RESUMEN
There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis of α -synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some familial PD. In sporadic PD, α -synuclein aggregation may interfere with mitochondrial function, and this might be further exacerbated by leucine-rich repeat kinase 2 (LRRK2). The majority of these findings have been obtained in Drosophila and cell cultures, whereas the objective of this paper is to discuss our recent results on the axonal pathology of brains derived from transgenic mice expressing α -synuclein or DLB-linked P123H ß -synuclein. In line with the current view of the pathogenesis of sporadic PD, mitochondria abnormally accumulated in α -synuclein/LRRK2-immunopositive axonal swellings in mice expressing α -synuclein. Curiously, neither mitochondria nor LRRK2 was present in the swellings of mice expressing P123H ß -synuclein, suggesting that α - and ß -synuclein might play differential roles in the mitochondrial pathology of α -synucleinopathies.