RESUMEN
Several studies conducted in patients with Parkinson's disease have reported that the degeneration of substantia nigra dopaminergic neurons, which are essential for motor control, is associated with the loss of hypothalamic orexin neurons, which are involved in sleep regulation. In order to better explore the mutual interactions between these two systems, we wished to determine in macaques: (i) if the two orexin peptides, orexin-A and orexin-B, are distributed in the same hypothalamic cells and if they are localized in nerve terminals that project onto nigral dopaminergic neurons, and (ii) if there is a loss of orexin neurons in the hypothalamus and of orexin fibers innervating nigral dopaminergic neurons in macaques rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. We showed that virtually all cells stained for orexin-A in the hypothalamus co-expressed orexin-B. Numerous terminals stained for both orexin-A and orexin-B immunoreactivity that innervated the whole extent of the ventral tegmental area and substantia nigra pars compacta were found in close proximity to tyrosine hydroxylase-immunoreactive dendrites. These data indicate that orexin-A and orexin-B peptides are in a position to play a role in controlling the activity of nigral dopaminergic neurons. However, no loss of orexin-A or orexin-B neurons in the hypothalamus and no loss of orexin fibers in the substantia nigra pars compacta was found in MPTP-treated macaques when compared with control macaques. We conclude that a relatively selective dopaminergic lesion, such as that performed in MPTP-treated macaques, is not sufficient to induce a loss of hypothalamic orexin neurons.
Asunto(s)
Hipotálamo/patología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Intoxicación por MPTP/patología , Neuronas/patología , Neuropéptidos/metabolismo , Sustancia Negra/patología , Animales , Recuento de Células , Muerte Celular , Hipotálamo/metabolismo , Inmunohistoquímica , Intoxicación por MPTP/metabolismo , Macaca fascicularis , Vías Nerviosas/metabolismo , Vías Nerviosas/patología , Neuronas/metabolismo , Orexinas , Porción Compacta de la Sustancia Negra/metabolismo , Porción Compacta de la Sustancia Negra/patología , Fotomicrografía , Sustancia Negra/metabolismo , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/patologíaRESUMEN
Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD). For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs with bee venom was protective in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In particular, a specific component of bee venom, apamin, has previously been shown to have protective effects on dopaminergic neurons in vitro. However, no information regarding a potential protective action of apamin in animal models of PD is available to date. The specific goals of the present study were to (i) establish that the protective effect of bee venom for dopaminergic neurons is not restricted to acupoint stimulation, but can also be observed using a more conventional mode of administration and to (ii) demonstrate that apamin can mimic the protective effects of a bee venom treatment on dopaminergic neurons. Using the chronic mouse model of MPTP/probenecid, we show that bee venom provides sustained protection in an animal model that mimics the chronic degenerative process of PD. Apamin, however, reproduced these protective effects only partially, suggesting that other components of bee venom enhance the protective action of the peptide.
Asunto(s)
Apamina/farmacología , Venenos de Abeja/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/prevención & control , Puntos de Acupuntura , Animales , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Intoxicación por MPTP/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
We have examined whether degeneration of nigrostriatal dopaminergic neurons causes dysfunction of both the basal ganglia-thalamic and cerebello-thalamic pathways. Changes in the activity of thalamic neurons receiving input from the basal ganglia or the cerebellum were examined in two models of Parkinson's disease, 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Metabolic activity of the neurons was evaluated at the cellular level by quantitative in situ hybridization, using the expression of messenger RNA for subunit I of cytochrome oxidase (COI), encoded by the mitochondrial genome, as the marker. COI mRNA expression decreased significantly in thalamocortical neurons receiving input from the substantia nigra (-50.6%) or the cerebellum (-45%) in 6-OHDA-lesioned rats compared with controls. The decrease was observed in all thalamic neurons whether or not they were retrogradely labelled with a tracer injected into the motor cortex. Similarly, COI mRNA expression decreased in projection neurons and interneurons of the thalamus receiving input from the substantia nigra (-39 and -38%, respectively), the internal pallidum (-20 and -42.4%, respectively) and the cerebellum (-36.2 and -50%, respectively) of MPTP-treated monkeys compared with controls. These decreases in COI mRNA levels show that nigrostriatal denervation results in a decrease in the metabolic activity of thalamic neurons in the territories innervated by the substantia nigra, pallidum and cerebellum, which in turn is indicative of a decrease in their neuronal activity. The decrease did not concern the entire thalamus, however, since metabolic activity was unchanged in two thalamic nuclei considered to be limbic structures, the laterodorsal nucleus in 6-OHDA-lesioned rats and the anterior nucleus in MPTP-treated monkeys. Hypoactivity of both the basal ganglia-thalamic and cerebellar-thalamic pathways might therefore be implicated in the development of parkinsonian symptoms.
Asunto(s)
Ganglios Basales/metabolismo , Cerebelo/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Tálamo/metabolismo , Animales , Cuerpo Estriado/enzimología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Dopaminérgicos , Complejo IV de Transporte de Electrones/análisis , Haplorrinos , Inmunohistoquímica/métodos , Hibridación in Situ/métodos , Interneuronas/metabolismo , Vías Nerviosas/metabolismo , Oxidopamina , ARN Mensajero/análisis , Ratas , Sustancia Negra/enzimología , Simpaticolíticos , Tirosina 3-Monooxigenasa/análisisRESUMEN
Different analyses of neuronal activity in primate models of Parkinson's disease (PD) have resulted in two different views on the effects of dopamine depletion. The first is based on the higher firing rate and bursty firing pattern, and assumes that dopamine depletion results in a hyperactivity of basal ganglia (BG) output structures. The second is based on the less-specific responses to passive joint manipulation and the excessive correlations between neuronal discharges, and assumes that dopamine depletion results in a loss of functional segregation in cortico-BG circuits. The aim of the present study was to test out the predictions of these two different views on thalamic neuronal activity. Three male vervet monkeys (Cercopithecus aethiops) were progressively intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal activities were characterized using standard analyses (firing rates and patterns, receptive fields, and cross-correlations) and compared between the normal, asymptomatic (before the stabilization of motor symptoms), and parkinsonian (with persistent akinesia and rigidity) stages of MPTP intoxication. The pallidonigral thalamus (receiving projections from the BG) was characterized in both the asymptomatic and parkinsonian states by (1) an unchanged firing rate and pattern and (2) a proliferation of nonspecific neurons and correlated pairs. In contrast, the cerebellar thalamus (receiving projections from the cerebellum), was characterized by no change (asymptomatic state) or minor changes (symptomatic state). Thus the major dysfunction after dopamine depletion appeared to be the loss of functional segregation within cortico-BG circuits, which could also be at the heart of parkinsonian pathophysiology.
Asunto(s)
Ganglios Basales/fisiopatología , Dopamina/deficiencia , Intoxicación por MPTP/fisiopatología , Neuronas/fisiología , Trastornos Parkinsonianos/fisiopatología , Tálamo/fisiopatología , Potenciales de Acción , Animales , Biomarcadores , Chlorocebus aethiops , Electrodos Implantados , Electromiografía , Masculino , Modelos Neurológicos , Proteínas del Tejido Nervioso/análisis , Tirosina 3-Monooxigenasa/análisisRESUMEN
In Guadeloupe, epidemiological data have linked atypical parkinsonism with fruit and herbal teas from plants of the Annonaceae family, particularly Annona muricata. These plants contain a class of powerful, lipophilic complex I inhibitors, the annonaceous acetogenins. To determine the neurotoxic potential of these substances, we administered annonacin, the major acetogenin of A. muricata, to rats intravenously with Azlet osmotic minipumps (3.8 and 7.6 mg per kg per day for 28 days). Annonacin inhibited complex I in brain homogenates in a concentration-dependent manner, and, when administered systemically, entered the brain parenchyma, where it was detected by matrix-associated laser desorption ionization-time of flight mass spectrometry, and decreased brain ATP levels by 44%. In the absence of evident systemic toxicity, we observed neuropathological abnormalities in the basal ganglia and brainstem nuclei. Stereological cell counts showed significant loss of dopaminergic neurones in the substantia nigra (-31.7%), and cholinergic (-37.9%) and dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32)-immunoreactive GABAergic neurones (-39.3%) in the striatum, accompanied by a significant increase in the number of astrocytes (35.4%) and microglial cells (73.4%). The distribution of the lesions was similar to that in patients with atypical parkinsonism. These data are compatible with the theory that annonaceous acetogenins, such as annonacin, might be implicated in the aetiology of Guadeloupean parkinsonism and support the hypothesis that some forms of parkinsonism might be induced by environmental toxins.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Furanos/toxicidad , Lactonas/toxicidad , Enfermedades Neurodegenerativas/inducido químicamente , Extractos Vegetales/toxicidad , Sustancia Negra/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Recuento de Células , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Furanos/administración & dosificación , Gliosis/inducido químicamente , Gliosis/patología , Guadalupe , Infusiones Intravenosas , Lactonas/administración & dosificación , Masculino , Mitocondrias/enzimología , Enfermedades Neurodegenerativas/enzimología , Enfermedades Neurodegenerativas/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Trastornos Parkinsonianos/etiología , Extractos Vegetales/administración & dosificación , Ratas , Ratas Endogámicas Lew , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
Two biochemical deficits have been described in the substantia nigra in Parkinson's disease, decreased activity of mitochondrial complex I and reduced proteasomal activity. We analysed interactions between these deficits in primary mesencephalic cultures. Proteasome inhibitors (epoxomicin, MG132) exacerbated the toxicity of complex I inhibitors [rotenone, 1-methyl-4-phenylpyridinium (MPP+)] and of the toxic dopamine analogue 6-hydroxydopamine, but not of inhibitors of mitochondrial complex II-V or excitotoxins [N-methyl-d-aspartate (NMDA), kainate]. Rotenone and MPP+ increased free radicals and reduced proteasomal activity via adenosine triphosphate (ATP) depletion. 6-hydroxydopamine also increased free radicals, but did not affect ATP levels and increased proteasomal activity, presumably in response to oxidative damage. Proteasome inhibition potentiated the toxicity of rotenone, MPP+ and 6-hydroxydopamine at concentrations at which they increased free radical levels >/= 40% above baseline, exceeding the cellular capacity to detoxify oxidized proteins reduced by proteasome inhibition, and also exacerbated ATP depletion caused by complex I inhibition. Consistently, both free radical scavenging and stimulation of ATP production by glucose supplementation protected against the synergistic toxicity. In summary, proteasome inhibition increases neuronal vulnerability to normally subtoxic levels of free radicals and amplifies energy depletion following complex I inhibition.
Asunto(s)
Cisteína Endopeptidasas/metabolismo , Complejos Multienzimáticos/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , Neuronas/metabolismo , Trastornos Parkinsonianos/metabolismo , 1-Metil-4-fenilpiridinio/toxicidad , Adenosina Trifosfato/metabolismo , Animales , Muerte Celular , Células Cultivadas , Relación Dosis-Respuesta a Droga , Complejo I de Transporte de Electrón , Inhibidores Enzimáticos/toxicidad , Mesencéfalo/citología , Mesencéfalo/embriología , Complejos Multienzimáticos/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Neuronas/patología , Neurotoxinas/toxicidad , Oxidación-Reducción/efectos de los fármacos , Trastornos Parkinsonianos/patología , Complejo de la Endopetidasa Proteasomal , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Rotenona/toxicidad , Desacopladores/toxicidadRESUMEN
This study presents an analysis of the distribution and organization pattern of axons originating from the substantia nigra pars reticulata and projecting to the thalamus in monkeys. Biotin dextran amine was iontophoretically injected into different parts of the substantia nigra pars reticulata of monkeys (African green monkeys and macaques). In whatever part of the substantia nigra the injection was made, numerous axonal endings were found to be distributed within different thalamic regions: the ventral anterior nucleus and mainly its magnocellular part, the most ventromedial part of the ventral lateral nucleus, and the mediodorsal and parafascicular nuclei. Moreover, the nigrothalamic projection appeared to be topographically organized. Ten anterogradely labeled axons were reconstructed from serial sections. The axons terminated in three to six terminal fields per axon located in a relatively small portion of only one thalamic region. These terminal fields were variable in size and comprised 4-43 very thin, varicose branches. They consisted either of different axonal branches of the same axon or of different axons and covered 10-31 thalamic cell bodies. These findings demonstrate that the overall morphological organization of individual nigral axons is complex and allows single axons to influence thalamic neurons via a combination of divergent, convergent, and amplification processes.