RESUMEN
The loss of the neurotransmitter noradrenaline occurs constantly in Parkinson's disease. This is supposed to worsen disease progression, either by increasing the vulnerability of dopamine-containing neurons or by reducing the recovery once they are damaged. Novel data also show that the loss of noradrenergic innervation facilitates the onset of dyskinesia occurring in Parkinsonian patients during dopamine replacement therapy. In the first part of the manuscript we review the evidence showing the loss of the noradrenergic system as an early event in the natural history of Parkinsonism. This evidence is discussed in light of novel reports showing the deleterious effects produced by the noradrenergic deficit on the survival of nigral dopamine neurons. In particular, we analyze the biochemical and morphological changes produced in the nigrostriatal system by the loss of endogenous noradrenaline. In a dedicated paragraph we specifically evaluate the cross affinity between dopamine and noradrenaline systems. In fact, this is critical during dopamine/noradrenaline replacement therapy in Parkinson's disease. In the last part, we overview novel therapeutic approaches aimed at restoring the activation of noradrenaline receptors to reduce the dyskinesia occurring in the treatment of Parkinson's disease.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Dopamina/metabolismo , Norepinefrina/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Animales , Antiparkinsonianos/efectos adversos , Progresión de la Enfermedad , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/prevención & control , Humanos , Levodopa/efectos adversos , Levodopa/uso terapéutico , Locus Coeruleus/patología , Locus Coeruleus/fisiopatología , Neuronas/parasitología , Neuronas/fisiología , Receptores Adrenérgicos/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMEN
In recent years several clinical and research findings have demonstrated the involvement of the presynaptic protein alpha-synuclein in a variety of neurodegenerative disorders which are known as synucleinopathies. Although the function of this protein in the physiology of the cell remains unknown, it is evident that both genetic alterations or a mere overexpression of the native molecule produces a degeneration of nigral dopamine-containing neurons leading to movement disorders, as demonstrated in inherited Parkinson's disease. In the present study, we investigated whether widely abused drugs such as methamphetamine and methylenedioxymethamphetamine (ecstasy), which are known to damage the nigrostriatal dopamine pathway of mice, increase the expression of alpha-synuclein within dopamine neurons of the substantia nigra pars compacta. The results of this study demonstrate that nigrostriatal dopamine denervation and occurrence of intracellular inclusions in nigral neurons produced by amphetamine derivatives are related to increased expression of alpha-synuclein within dopamine neurons of the substantia nigra. This lends substance to the hypothesis that increased amounts of native alpha-synuclein may be per se a detrimental factor for the dopamine neurons.
Asunto(s)
Anfetamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Cuerpos de Inclusión/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Sustancia Negra/citología , Ácido 3,4-Dihidroxifenilacético/metabolismo , Inhibidores de Captación Adrenérgica/farmacología , Alcanos/farmacología , Amidas/farmacología , Análisis de Varianza , Animales , Western Blotting/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato Descarboxilasa/metabolismo , Ácido Homovanílico/metabolismo , Inmunohistoquímica/métodos , Cuerpos de Inclusión/metabolismo , Isoenzimas/metabolismo , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión/métodos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Neuronas/metabolismo , Neuronas/ultraestructura , Sustancia Negra/efectos de los fármacos , Sinucleínas , Tirosina 3-Monooxigenasa/metabolismo , alfa-SinucleínaRESUMEN
This brief paper analyzes a few degenerative diseases expressing as movement disorders and featuring at sub-cellular level the presence of neuronal inclusions in selective brain regions. We will first draw a short draft of representative neurological diseases featuring inclusion bodies by describing the type of inclusions occurring in various disorders and analyzing both common features and distinctive aspects. As a further step, we move from the bed to the bench side discussing recent developments obtained from experimental models of these disorders which shed new light into the cause and progression of neuronal inclusions, thus helping to understand the pathophysiology of neuronal degeneration underlying movement disorders. In line with this, we will focus on recent studies which led to reproduce neuronal inclusions in vivo and in vitro by manipulating selective cellular structures/enzymatic pathways. In this way, we will try to encompass the dynamics of inclusion formation based on their fine ultrastructure and the analysis of the molecular components as well as their subcellular compartmentalization trying to relate the dynamics of inclusion formation and the pathophysiology of the disease process. An emphasis will be made on the ubiquitin proteasome system and Parkinson's disease where the analysis of neuronal inclusions enlightened potential therapeutic strategies to occlude the progression of this neuronal degeneration featured by movement disorders.
Asunto(s)
Cuerpos de Inclusión/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/metabolismo , Animales , Modelos Animales de Enfermedad , Dopamina/fisiología , Humanos , Cuerpos de Inclusión/patología , Modelos Neurológicos , Proteínas del Tejido Nervioso/metabolismo , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Enfermedades Neurodegenerativas/clasificación , Enfermedades Neurodegenerativas/genética , Neuronas/patología , Sinucleínas , Ubiquitina/metabolismoRESUMEN
The purpose of this study was to investigate for difference in the prevalence of mood disorders between patients with different painful temporomandibular disorders (TMD). After a sample size necessary for the study was calculated, 60 patients with a painful TMD were selected and divided into the following groups: myofascial pain (n=20), temporomandibular joint (TMJ) pain (n=18), combined myofascial and TMJ pain (n=22). Two distinct comparison groups were selected: subjects with a nonpainful TMD (n=25) and TMD-free subjects (n=29). All participants filled out a self-report validated instrument (MOODS-SR) to evaluate psychopathological symptoms related to mood disturbances. A one-way analysis of variance (ANOVA) with Bonferroni's post hoc test for multiple comparisons was performed to investigate for significant differences among the groups. The three groups of patients with painful TMD scored significantly higher than comparison groups in all MOODS-SR domains investigating depression, but no difference was shown between subjects with myofascial pain and those with TMJ pain. No significant differences among the groups emerged for the presence of manic symptoms, indicating that depressive disorders associated with TMD are not an expression of a more complex manic depressive illness. The study concluded that the presence of depressive symptoms in TMD patients seems to be related to the presence of a painful condition and seems to be unrelated to the location of pain. Furthermore, depressive disturbances in painful TMD patients affect the whole spectrum of depressive psychopathology.
Asunto(s)
Trastornos del Humor/psicología , Trastornos de la Articulación Temporomandibular/psicología , Actividades Cotidianas , Adulto , Afecto , Análisis de Varianza , Artralgia/psicología , Trastorno Bipolar/psicología , Ritmo Circadiano , Cognición , Depresión/psicología , Trastorno Depresivo/psicología , Dolor Facial/psicología , Femenino , Humanos , Masculino , Osteoartritis/psicología , Síndrome de la Disfunción de Articulación Temporomandibular/psicologíaRESUMEN
Gender differences in the social anxiety spectrum and their correlation with other psychopathological features were analyzed in 520 students by using two questionnaires: the Social Anxiety Spectrum Self-Report (SHY-SR), which explores social anxiety spectrum, and the General Spectrum Measure (GSM), which explores panic-agoraphobia, mood, obsessive-compulsive, and eating-behavior features. Mean SHY-SR total score was significantly higher in women than in men, and gender differences were particularly pronounced for interpersonal sensitivity domain. Likewise, GSM scores were higher in women, except for the manic section. The SHY-SR domains correlated significantly with all GSM sections, except for the manic section. In conclusion, women reported more symptoms than men (who belonged to different psychopathologic dimensions) and displayed a profile of social anxiety spectrum that differs quantitatively but not qualitatively from the men's profile. The correlation between social anxiety spectrum and other psychopathological features mirrors previous findings concerning the high comorbidity of axis-I social anxiety disorder.