RESUMEN
The motor symptoms of Parkinson's disease are due to the progressive degeneration of dopaminergic neurons in the substantia nigra. Multiple neuroinflammatory processes are exacerbated in Parkinson's disease, including glial-mediated reactions, increased expression of proinflammatory substances, and lymphocytic infiltration, particularly in the substantia nigra. Neuroinflammation is also implicated in the neurodegeneration and consequent behavioral symptoms of many Parkinson's disease animal models, although it is not clear whether these features emulate pathogenic steps in the genuine disorder or if some inflammatory features provide protective stress responses. Here, we compare and summarize findings on neuroinflammatory responses and effects on behavior in a wide range of toxin-based, inflammatory and genetic Parkinson's disease animal models.
Asunto(s)
Modelos Animales de Enfermedad , Inflamación , Enfermedad de Parkinson , Animales , Inflamación/inmunología , Inflamación/patología , Inflamación/fisiopatología , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Neuronal expression of major histocompatibility complex I (MHC-I) has been implicated in developmental synaptic plasticity and axonal regeneration in the central nervous system (CNS), but recent findings demonstrate that constitutive neuronal MHC-I can also be involved in neurodegenerative diseases by playing a neuroinflammtory role. Recent reports demonstrate its expression in vitro and in human postmortem samples and support a role in neurodegeneration involving proinflammatory cytokines, activated microglia and increased cytosolic oxidative stress. Major histocompatibility complex I may be important for both normal development and pathogenesis of some CNS diseases including Parkinson's.
RESUMEN
BACKGROUND: An accumulating body of evidence points to the significance of neuroinflammation and immunogenetics in schizophrenia, and an imbalance of cytokines in the central nervous system (CNS) has been suggested to be associated with the disorder. Munc18-overexpressing mice (Munc18-OE) have provided a model for the study of the alterations that may underlie the symptoms of subjects with schizophrenia. The aim of the present study was to elucidate the involvement of neuroinflammation and cytokine imbalance in this model. METHODS: Cytokines were evaluated in the cortex and the striatum of Munc18-OE and wild-type (WT) mice by enzyme-linked immunosorbent assay (ELISA). Protein levels of specific microglia and macrophage, astrocytic and neuroinflammation markers were quantified by western blot in the cortex and the striatum of Munc18-OE and WT mice. RESULTS: Each cytokine evaluated (Interferon-gamma (IFN-γ), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-2 (IL-2) and CCL2 chemokine) was present at higher levels in the striatum of Munc18-OE mice than WT. Cortical TNF-α and IL-2 levels were significantly lower in Munc18-OE mice than WT mice. The microglia and macrophage marker CD11b was lower in the cortexes of Munc18-OE mice than WT, but no differences were observed in the striatum. Glial Fibrillary Acidic Protein (GFAP) and Nuclear Factor-kappaB (NF-κB)p65 levels were not different between the groups. Interleukin-1beta (IL-1ß) and IL-6 levels were beneath detection limits. CONCLUSIONS: The disrupted levels of cytokines detected in the brain of Munc18-OE mice was found to be similar to clinical reports and endorses study of this type for analysis of this aspect of the disorder. The lower CD11b expression in the cortex but not in the striatum of the Munc18-OE mice may reflect differences in physiological activity. The cytokine expression pattern observed in Munc18-OE mice is similar to a previously published model of schizophrenia caused by maternal immune activation. Together, these data suggest a possible role for an immune imbalance in this disorder.
Asunto(s)
Citocinas/metabolismo , Proteínas Munc18/metabolismo , Esquizofrenia/metabolismo , Transducción de Señal/fisiología , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Proteína Ácida Fibrilar de la Glía , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Munc18/genética , FN-kappa B/metabolismo , Esquizofrenia/genética , Esquizofrenia/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Subsets of rodent neurons are reported to express major histocompatibility complex class I (MHC-I), but such expression has not been reported in normal adult human neurons. Here we provide evidence from immunolabel, RNA expression and mass spectrometry analysis of postmortem samples that human catecholaminergic substantia nigra and locus coeruleus neurons express MHC-I, and that this molecule is inducible in human stem cell-derived dopamine (DA) neurons. Catecholamine murine cultured neurons are more responsive to induction of MHC-I by gamma-interferon than other neuronal populations. Neuronal MHC-I is also induced by factors released from microglia activated by neuromelanin or alpha-synuclein, or high cytosolic DA and/or oxidative stress. DA neurons internalize foreign ovalbumin and display antigen derived from this protein by MHC-I, which triggers DA neuronal death in the presence of appropriate cytotoxic T cells. Thus, neuronal MHC-I can trigger antigenic response, and catecholamine neurons may be particularly susceptible to T-cell-mediated cytotoxic attack.
Asunto(s)
Neuronas Adrenérgicas/metabolismo , Neuronas Dopaminérgicas/metabolismo , Genes MHC Clase I , Antígenos de Histocompatibilidad Clase I/genética , Locus Coeruleus/metabolismo , Microglía/metabolismo , ARN Mensajero/metabolismo , Sustancia Negra/metabolismo , Neuronas Adrenérgicas/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Animales , Supervivencia Celular , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Femenino , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/efectos de los fármacos , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Interferón gamma/farmacología , Masculino , Melaninas/metabolismo , Ratones , Persona de Mediana Edad , Estrés Oxidativo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , ARN Mensajero/efectos de los fármacos , Linfocitos T Citotóxicos , alfa-Sinucleína/metabolismoRESUMEN
AIMS: The NADPH oxidases constitute a major source of superoxide anion (·O2(-)) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by transforming growth factor-ß1 (TGF-ß1). We investigated whether a chronic treatment with P144, a peptide synthesized from type III TGF-ß1 receptor, inhibited NADPH oxidases in the renal cortex of spontaneously hypertensive rats (SHR). RESULTS: Here, we show that chronic administration of P144 significantly reduced the NADPH oxidase expression and activity as well as the oxidative stress observed in control vehicle-treated SHR (V-SHR). In addition, P144 was also able to reduce the significant increase in the renal fibrosis and in mRNA expression of different components of collagen metabolism, as well as in the levels of connective tissue growth factor observed in V-SHR. Finally, TGF-ß1-stimulated NRK52E exhibited a significant increase in NADPH oxidase expression and activity as well as a TGF-ß1-dependent intracellular pathway that were inhibited in the presence of P144. INNOVATION: Our experimental evidence suggests that reversing oxidative stress may be therapeutically useful in preventing fibrosis-associated renal damage. We show here that (i) the TGF-ß1-NADPH oxidases axis is crucial in the development of fibrosis in an experimental hypertensive renal disease animal model, and (ii) the use of P144 reverses TGF-ß1-dependent NADPH oxidase activity; thus, P144 may be considered a novel therapeutic tool in kidney disease associated with hypertension. CONCLUSION: We demonstrate that P144 inhibits NADPH oxidases and prevents oxidative stress in kidneys from hypertensive rats. Our data also suggest that these effects are associated with the renal antifibrotic effect of P144.
Asunto(s)
Riñón/efectos de los fármacos , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/química , Fragmentos de Péptidos/uso terapéutico , Proteoglicanos/química , Receptores de Factores de Crecimiento Transformadores beta/química , Receptores de Factores de Crecimiento Transformadores beta/uso terapéutico , Animales , Fibrosis/metabolismo , Fibrosis/prevención & control , Riñón/metabolismo , Riñón/patología , Masculino , Ratas , Ratas Endogámicas SHR , Transducción de Señal/efectos de los fármacosRESUMEN
NADPH oxidases constitute a major source of superoxide anion (·O(2)(-)) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by TGF-ß 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-ß 1 receptor, significantly reduced the cardiac NADPH oxidase expression and activity as well as in the nitrotyrosine levels observed in control spontaneously hypertensive rats (V-SHR) to levels similar to control normotensive Wistar Kyoto rats. In addition, P144 was also able to reduce the significant increases in the expression of collagen type I protein and mRNA observed in hearts from V-SHR. In addition, positive correlations between collagen expression, NADPH oxidase activity, and nitrotyrosine levels were found in all animals. Finally, TGF-ß 1-stimulated Rat-2 exhibited significant increases in NADPH oxidase activity that was inhibited in the presence of P144. It could be concluded that the blockade of TGF-ß 1 with P144 inhibited cardiac NADPH oxidase in SHR, thus adding new data to elucidate the involvement of this enzyme in the profibrotic actions of TGF-ß 1.
Asunto(s)
Hipertensión/enzimología , NADPH Oxidasas/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Animales , Presión Sanguínea/efectos de los fármacos , Línea Celular , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibroblastos/efectos de los fármacos , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Miocardio/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasa 4 , NADPH Oxidasas/genética , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/uso terapéutico , Ratas , Ratas Endogámicas WKY , Receptores de Factores de Crecimiento Transformadores beta/uso terapéutico , Factor de Crecimiento Transformador beta1/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
mTOR is a regulator of cell growth and survival, protein synthesis-dependent synaptic plasticity, and autophagic degradation of cellular components. When triggered by mTOR inactivation, macroautophagy degrades long-lived proteins and organelles via sequestration into autophagic vacuoles. mTOR further regulates synaptic plasticity, and neurodegeneration occurs when macroautophagy is deficient. It is nevertheless unknown whether macroautophagy modulates presynaptic function. We find that the mTOR inhibitor rapamycin induces formation of autophagic vacuoles in prejunctional dopaminergic axons with associated decreased axonal profile volumes, synaptic vesicle numbers, and evoked dopamine release. Evoked dopamine secretion was enhanced and recovery was accelerated in transgenic mice in which macroautophagy deficiency was restricted to dopaminergic neurons; rapamycin failed to decrease evoked dopamine release in the striatum of these mice. Macroautophagy that follows mTOR inhibition in presynaptic terminals, therefore, rapidly alters presynaptic structure and neurotransmission.
Asunto(s)
Autofagia/genética , Encéfalo/citología , Regulación de la Expresión Génica/genética , Proteínas Asociadas a Microtúbulos/genética , Terminales Presinápticos/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/análogos & derivados , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Análisis de Varianza , Animales , Autofagia/efectos de los fármacos , Proteína 7 Relacionada con la Autofagia , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Dopamina/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 , Electroquímica , Regulación de la Expresión Génica/efectos de los fármacos , Genotipo , Inmunosupresores/farmacología , Técnicas In Vitro , Masculino , Ratones , Ratones Transgénicos , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos/metabolismo , Terminales Presinápticos/ultraestructura , ARN Mensajero/genética , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The patterns of axonal collateralization of nucleus accumbens (Acb) projection neurons were investigated in the rat by means of single-axon tracing techniques using the anterograde tracer biotinylated dextran amine. Seventy-three axons were fully traced, originating from either the core (AcbC) or shell (AcbSh) compartment, as assessed by differential calbindin D28k-immunoreactivity. Axons from AcbC and AcbSh showed a substantial segregation in their targets; target areas were either exclusively or preferentially innervated from AcbC or AcbSh. Axon collaterals in the subthalamic nucleus were found at higher than expected frequencies; moreover, these originated exclusively in the dorsal AcbC. Intercompartmental collaterals were observed from ventral AcbC axons into AcbSh, and likewise, interconnections at pallidal and mesencephalic levels were also observed, although mostly from AcbC axons toward AcbSh targets, possibly supporting crosstalk between the two subcircuits at several levels. Cell somata giving rise to short-range accumbal axons, projecting to the ventral pallidum (VP), were spatially intermingled with others, giving rise to long-range axons that innervated VP and more caudal targets. This anatomical organization parallels that of the dorsal striatum and provides the basis for possible dual direct and indirect actions from a single axon on either individual or small sets of neurons.
Asunto(s)
Axones/fisiología , Neuronas/citología , Núcleo Accumbens/citología , 3,3'-Diaminobencidina/metabolismo , Acetilcolinesterasa/metabolismo , Potenciales de Acción/fisiología , Animales , Calbindina 1 , Calbindinas , Electrofisiología/métodos , Encefalina Leucina/metabolismo , Masculino , Neuronas/fisiología , Ratas , Ratas Wistar , Proteína G de Unión al Calcio S100/metabolismo , Sustancia P/metabolismoRESUMEN
The most caudally located dopaminergic (DA) ventral tier neurons of the substantia nigra pars compacta (SNc) form typical cell clusters that are deeply embedded in the substantia nigra pars reticulata (SNr). Here we examine the efferent projections of 35 neurons located in the SNr region where these SNc cell clusters reside. The neuronal cell body was injected with biotinylated dextran amine so as to trace each complete axon in the sagittal or the coronal plane. Electrophysiological guidance guaranteed that the tracer was ejected among neurons displaying a typical SNc discharge pattern. Furthermore, double immunofluorescence and immunohistochemical labeling ensured that the tracer deposits were placed within the DA cell clusters. Three types of projection neurons occurred in the SNc ventral tier cell cluster region: type I neurons, projecting to basal ganglia; type II neurons, targeting both the basal ganglia and thalamus; and type III neurons, projecting only to the thalamus. The striatum was targeted by most of the type I and II neurons and the innervation reached both the striosome/subcallosal streak and matrix compartments. Many nigrostriatal fibers provided collaterals to the globus pallidus and, less frequently, to the subthalamic nucleus. At a thalamic level, type II and III neurons preferentially targeted the reticular, ventral posterolateral, and ventral medial nuclei. Our results reveal that the SNr region where DA ventral tier cell clusters reside harbors neurons projecting to the basal ganglia and/or the thalamus, thus suggesting that neurodegeneration of nigral neurons in Parkinson's disease might affect various extrastriatal basal ganglia structures and multiple thalamic nuclei.
Asunto(s)
Ganglios Basales/anatomía & histología , Neuronas/citología , Sustancia Negra/anatomía & histología , Tálamo/anatomía & histología , Animales , Axones/fisiología , Ganglios Basales/fisiología , Biotina/análogos & derivados , Cuerpo Estriado/anatomía & histología , Cuerpo Estriado/fisiología , Dextranos , Femenino , Técnica del Anticuerpo Fluorescente , Globo Pálido/anatomía & histología , Globo Pálido/fisiología , Inmunohistoquímica , Masculino , Microelectrodos , Trazadores del Tracto Neuronal , Neuronas/fisiología , Ratas , Ratas Wistar , Sustancia Negra/fisiología , Núcleo Subtalámico/anatomía & histología , Núcleo Subtalámico/fisiología , Tálamo/fisiologíaRESUMEN
We have examined the morphology of the somatodendritic domain of projection neurons located in different sectors of rat substantia nigra pars reticulata (SNr) or having distinct axonal arborizations. Forty-three neurons - 23 located in the dorsal half and 20 in the ventral half of SNr - were injected with biotinylated dextran amine and their somatodendritic domain was reconstructed from serial sagittal sections with a camera lucida. The axonal arborization of 14 neurons was also reconstructed. Dorsally located SNr neurons had a larger perikaryon, a higher number of primary dendrites and a more extensive dendritic arbor than the ventrally located ones. However, irrespective of their location in the SNr, the somatodendritic domain was always longer along the rostrocaudal axis than along the dorsoventral and mediolateral axes. Specific correlations between somatodendritic morphology and axonal arborization could be established for some SNr neurons, but among SNr neurons with similar efferent projections, those lying dorsally always exhibited a larger perikaryon and a more widespread dendritic arbor than those located ventrally. These results indicate that the morphology of the somatodendritic domain of SNr projection neurons is related to the location of their perikaryon within the structure rather than to the pattern of their axonal projections.
Asunto(s)
Dendritas/fisiología , Vías Nerviosas/citología , Neuronas/citología , Sustancia Negra/fisiología , Sinapsis/fisiología , Análisis de Varianza , Animales , Recuento de Células/métodos , Femenino , Masculino , Neuronas/clasificación , Ratas , Ratas WistarRESUMEN
Axons from neurons of the rat substantia nigra pars reticulata (SNr) and pars lateralis (SNl) were traced after injecting their cell body with biotinylated dextran amine. Thirty-two single axons were reconstructed from serial sagittal sections with a camera lucida, whereas four other SNr axons were reconstructed in the coronal plane to determine whether they innervate the contralateral hemisphere. Four distinct types of SNr projection neurons were identified based on their main axonal targets: type I neurons that project to the thalamus; type II neurons that target the thalamus, the superior colliculus (SC), and the pedunculopontine tegmental nucleus (PPTg); type III neurons that project to the periaqueductal gray matter and the thalamus; and type IV neurons that target the deep mesencephalic nucleus (DpMe) and the SC. The axons of the SNl showed the same branching patterns as SNr axons of types I, II, and IV. The coronal reconstructions demonstrated that SNr neurons innervate the thalamus, the SC, and the DpMe bilaterally. At the thalamic level, SNr and SNl axons targeted preferentially the ventral medial, ventral lateral, paracentral, parafascicular, and mediodorsal nuclei. Axons reaching the SC arborized selectively within the deep layers of this structure. Our results reveal that the SNr and SNl harbor several subtypes of projection neurons endowed with a highly patterned set of axon collaterals. This organization allows single neurons of these output structures of the basal ganglia to exert a multifaceted influence on a wide variety of diencephalic and midbrain structures.