RESUMEN
An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of "homemade" methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the 'homemade' drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the 'homemade' mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the 'homemade' mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.
Asunto(s)
Enfermedades de los Ganglios Basales/inducido químicamente , Cuerpo Estriado/efectos de los fármacos , Manganeso/toxicidad , Propiofenonas/toxicidad , Sustancia Negra/efectos de los fármacos , Animales , Enfermedades de los Ganglios Basales/diagnóstico por imagen , Enfermedades de los Ganglios Basales/metabolismo , Enfermedades de los Ganglios Basales/patología , Conducta Animal , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Masculino , Manganeso/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Propiofenonas/administración & dosificación , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Methcathinone-induced Parkinsonism is a recently described extrapyramidal syndrome characterized by globus pallidus and substantia nigra lesions, which provides a unique model of basal ganglia dysfunction. We assessed motivated behaviour in this condition using a novel cost-benefit decision-making task, in which participants decided whether it was worth investing effort for reward. Patients showed a dissociation between reward and effort sensitivity, such that pallidonigral complex dysfunction caused them to become less sensitive to rewards, while normal sensitivity to effort costs was maintained.
Asunto(s)
Intoxicación por Manganeso/complicaciones , Motivación/fisiología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/psicología , Propiofenonas/efectos adversos , Recompensa , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Estudios de Casos y Controles , Toma de Decisiones/fisiología , Femenino , Humanos , Masculino , Motivación/efectos de los fármacos , Enfermedad de Parkinson Secundaria/diagnóstico por imagenRESUMEN
BACKGROUND: A permanent Parkinsonian syndrome occurs in intravenous abusers of the designer psychostimulant methcathinone (ephedrone). It is attributed to deposition of contaminant manganese, as reflected by characteristic globus pallidus hyperintensity on T1-weighted MRI. METHODS: We have investigated brain structure and function in methcathinone abusers (n = 12) compared to matched control subjects (n = 12) using T1-weighted structural and resting-state functional MRI. RESULTS: Segmentation analysis revealed significant (p < .05) subcortical grey matter atrophy in methcathinone abusers within putamen and thalamus bilaterally, and the left caudate nucleus. The volume of the caudate nuclei correlated inversely with duration of methcathinone abuse. Voxel-based morphometry showed patients to have significant grey matter loss (p < .05) bilaterally in the putamina and caudate nucleus. Surface-based analysis demonstrated nine clusters of cerebral cortical thinning in methcathinone abusers, with relative sparing of prefrontal, parieto-occipital, and temporal regions. Resting-state functional MRI analysis showed increased functional connectivity within the motor network of patients (p < .05), particularly within the right primary motor cortex. CONCLUSION: Taken together, these results suggest that the manganese exposure associated with prolonged methcathinone abuse results in widespread structural and functional changes affecting both subcortical and cortical grey matter and their connections. Underlying the distinctive movement disorder caused by methcathinone abuse, there is a more widespread pattern of brain involvement than is evident from the hyperintensity restricted to the basal ganglia as shown by T1-weighted structural MRI.
Asunto(s)
Encéfalo/efectos de los fármacos , Sustancia Gris/efectos de los fármacos , Trastornos Parkinsonianos/inducido químicamente , Propiofenonas/efectos adversos , Adulto , Atrofia/inducido químicamente , Encéfalo/patología , Encéfalo/fisiopatología , Estudios de Casos y Controles , Femenino , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Intoxicación por Manganeso/sangre , Intoxicación por Manganeso/etiología , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Trastornos Relacionados con Sustancias/patología , Trastornos Relacionados con Sustancias/fisiopatología , Adulto JovenRESUMEN
Perinatal stroke is a leading cause of congenital hemiparesis and neurocognitive deficits in children. Dysfunctions in the large-scale resting-state functional networks may underlie cognitive and behavioral disability in these children. We studied resting-state functional connectivity in patients with perinatal stroke collected from the Estonian Pediatric Stroke Database. Neurodevelopment of children was assessed by the Pediatric Stroke Outcome Measurement and the Kaufman Assessment Battery. The study included 36 children (age range 7.6-17.9 years): 10 with periventricular venous infarction (PVI), 7 with arterial ischemic stroke (AIS), and 19 controls. There were no differences in severity of hemiparesis between the PVI and AIS groups. A significant increase in default mode network connectivity (FDR 0.1) and lower cognitive functions (p < 0.05) were found in children with AIS compared to the controls and the PVI group. The children with PVI had no significant differences in the resting-state networks compared to the controls and their cognitive functions were normal. Our findings demonstrate impairment in cognitive functions and neural network profile in hemiparetic children with AIS compared to children with PVI and controls. Changes in the resting-state networks found in children with AIS could possibly serve as the underlying derangements of cognitive brain functions in these children.