RESUMEN
Lysosomes are membrane-bound organelles that are responsible for degrading and recycling macromolecules. Lysosomal dysfunction occurs in enzymatic and non-enzymatic deficiencies, which result in abnormal accumulation of materials. Although lysosomal storage disorders affect different organs, the central nervous system is the most vulnerable. Evidence shows the role of lysosomal dysfunction in different neurodegenerative diseases, such as Niemann-Pick Type C disease, juvenile neuronal ceroid lipofuscinosis, Alzheimer's disease and Parkinson's disease. Lysosomal enzymes such as lysosomal acid phosphatase 2 (Acp2) play a critical role in mannose-6-phosphate removal and Acp2 controls molecular and cellular functions in the brain during development and adulthood. Acp2 is essential in cerebellar development, and mutations in this gene cause severe cerebellar neurodevelopmental and neurodegenerative disorders. In this mini-review, we highlight lysosomal dysfunctions in the pathogenesis of neurodevelopmental and/or neurodegenerative diseases with special attention to Acp2 dysfunction.
Asunto(s)
Fosfatasa Ácida/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Lisosomas/metabolismo , Animales , Humanos , Enfermedades por Almacenamiento Lisosomal/metabolismo , Enfermedades por Almacenamiento Lisosomal/patología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patologíaRESUMEN
The neuroimmune-endocrine dysfunction has been accepted as one of fundamental mechanisms contributing to the pathophysiology of psychiatric disorders including depression and anxiety. In this study, we aimed to evaluate the involvement of hypothalamic-pituitary-adrenal (HPA) axis, interleukin-1ß, and nitrergic system in mediating the negative behavioral impacts of juvenile social isolation stress (SIS) in male mice. We also investigated the possible protective effects of lithium on behavioral and neurochemical changes in socially isolated animals. Results showed that experiencing 4-weeks of juvenile SIS provoked depressive and anxiety-like behaviors that were associated with hyper responsiveness of HPA axis, upregulation of interleukin-1ß, and nitric oxide (NO) overproduction in the pre-frontal cortex and hippocampus. Administration of lithium (10 mg/kg) significantly attenuated the depressant and anxiogenic effects of SIS in behavioral tests. Lithium also restored the negative effects of SIS on cortical and hippocampal interleukin-1ß and NO as well as HPA axis deregulation. Unlike the neutralizing effects of l-arginine (NO precursor), administration of l-NAME (3 mg/kg) and aminoguanidine (20 mg/kg) potentiated the positive effects of lithium on the behavioral and neurochemical profile of isolated mice. In conclusion, our results revealed that juvenile SIS-induced behavioral deficits are associated with abnormalities in HPA-immune function. Also, we suggest that alleviating effects of lithium on behavioral profile of isolated mice may be partly mediated by mitigating the negative impact of NO on HPA-immune function.
Asunto(s)
Ansiolíticos/farmacología , Antidepresivos/farmacología , Trastornos de Ansiedad/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Compuestos de Litio/farmacología , Animales , Trastornos de Ansiedad/fisiopatología , Corticosterona/sangre , Trastorno Depresivo/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/crecimiento & desarrollo , Sistema Hipotálamo-Hipofisario/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/crecimiento & desarrollo , Sistema Hipófiso-Suprarrenal/metabolismo , Aislamiento Social , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/fisiopatologíaRESUMEN
The p38α mitogen-activated protein kinase (MAPK) is one of the serine/threonine kinases regulating a variety of biological processes, including cell-type specification, differentiation and migration. Previous in vitro studies using pharmacological inhibitors suggested that p38 MAPK is essential for oligodendrocyte (OL) differentiation and myelination. To investigate the specific roles of p38α MAPK in OL development and myelination in vivo, we generated p38α conditional knockout (CKO) mice under the PLP and nerve/glial antigen 2 (NG2) gene promoters, as these genes are specifically expressed in OL progenitor cells (OPCs). Our data revealed that myelin synthesis was completely inhibited in OLs differentiated from primary OPC cultures derived from the NG2 Cre-p38α CKO mouse brains. Although an in vivo myelination defect was not obvious after gross examination of these mice, electron microscopic analysis showed that the ultrastructure of myelin bundles was severely impaired. Moreover, the onset of myelination in the corpus callosum was delayed in the knockout mice compared with p38α fl/fl control mice. A delay in OL differentiation in the central nervous system was observed with concomitant downregulation in the expression of OPC- and OL-specific genes such as Olig1 and Zfp488 during early postnatal development. OPC proliferation was not affected during this time. These data indicate that p38α is a positive regulator of OL differentiation and myelination. Unexpectedly, we observed an opposite effect of p38α on remyelination in the cuprizone-induced demyelination model. The p38α CKO mice exhibited better remyelination capability compared with p38α fl/fl mice following demyelination. The opposing roles of p38α in myelination and remyelination could be due to a strong anti-inflammatory effect of p38α or a dual reciprocal regulatory action of p38α on myelin formation during development and on remyelination after demyelination.
Asunto(s)
Sistema Nervioso Central/enzimología , Enfermedades Desmielinizantes/enzimología , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Alelos , Animales , Diferenciación Celular/fisiología , Células Cultivadas , Sistema Nervioso Central/patología , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteína Quinasa 14 Activada por Mitógenos/genética , Neuroglía/enzimología , Neuroglía/patologíaRESUMEN
The cerebellar nuclei integrate inhibitory input from Purkinje cells with excitatory input from mossy and climbing fiber collaterals and are the sole cerebellar output. Numerous studies have shown that the cerebellar cortex is highly compartmentalized into hundreds of genetically determined, reproducible topographic units--transverse zones and parasagittal stripes--that can be identified through the expression patterns of numerous molecules. The Purkinje cell stripes project to the cerebellar nuclei. However, there is no known commensurate topographic complexity in the cerebellar nuclei. Rather, conventional anatomical descriptions identify four major subdivisions--the medial, anterior and posterior interposed, and lateral nuclei--together with a few intranuclear subdivisions. To begin to address the apparent complexity gap, we have used a panel of antigens and transgenes to reveal a reproducible molecular heterogeneity in the mouse cerebellar nuclei. Based on the differential expression patterns, singly and in combination, a new cerebellar nuclear topographic map has been constructed. This reveals the subdivision of the cerebellar nuclei into at least 12 reproducible expression domains. We hypothesize that such heterogeneity is the counterpart of the zones and stripes of the cerebellar cortex.
Asunto(s)
Núcleos Cerebelosos/anatomía & histología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Antígenos CD57/biosíntesis , Núcleos Cerebelosos/metabolismo , Fructosa-Bifosfato Aldolasa/biosíntesis , Expresión Génica , Proteínas de Transporte de Glicina en la Membrana Plasmática/biosíntesis , Proteínas de Transporte de Glicina en la Membrana Plasmática/genética , Proteínas Fluorescentes Verdes/genética , Inmunohistoquímica , Operón Lac , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/biosíntesis , Fosfolipasa C beta/biosíntesis , Proteínas Serina-Treonina Quinasas/biosíntesis , TransgenesRESUMEN
The mammalian cerebellum is composed of a highly reproducible array of transverse zones, each of which is subdivided into parasagittal stripes. By using a combination of Purkinje cell antigenic markers and afferent tracing, four transverse zones have been identified: the anterior zone (AZ: approximately lobules I-V), the central zone (CZ: approximately lobules VI-VII), the posterior zone (PZ: approximately lobules VIII-dorsal IX) and the nodular zone (NZ: approximately ventral lobule IX+lobule X). Neurofilament-associated antigen (NAA) is an epitope recognized by a monoclonal antibody, which is expressed strongly in association with neurofilaments. During perinatal cerebellar development, anti-NAA immunocytochemistry reveals novel features of cerebellar organization. In particular, the CZ is reproducibly subdivided into anterior and posterior components. Between embryonic day 17 and postnatal day 7 NAA immunoreactivity is expressed selectively by a parallel fiber bundle that is restricted to lobule VII, thereby distinguishing the CZ anterior (lobules VIa, b) from the CZ posterior (lobule VII). The novel restriction boundary at lobule VII/VIII, which is also reflected in the morphology of the external granular layer and aligns with a gap in the developing Purkinje cell layer, precedes the morphological appearance of the posterior superior fissure between lobules VIb and VII. In addition, afferent axons to the CZ terminate in an array of parasagittal stripes that is probably a specific climbing fiber projection. Thus, the transverse zone architecture of the mouse cerebellum is more complex than had previously been appreciated.
Asunto(s)
Cerebelo/anatomía & histología , Regulación del Desarrollo de la Expresión Génica/fisiología , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Neurofilamentos/metabolismo , Animales , Animales Recién Nacidos , Tipificación del Cuerpo/fisiología , Calbindinas , Cerebelo/embriología , Cerebelo/crecimiento & desarrollo , Embrión de Mamíferos , Epítopos/genética , Epítopos/metabolismo , Proteínas del Ojo/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Neuropéptidos/metabolismo , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box/metabolismo , Células de Purkinje/metabolismo , Proteínas Represoras/metabolismo , Proteína G de Unión al Calcio S100/metabolismoRESUMEN
The mammalian cerebellar cortex is highly compartmentalized. First, it is subdivided into four transverse expression domains: the anterior zone (AZ), the central zone (CZ), the posterior zone (PZ), and the nodular zone (NZ). Within each zone, the cortex is further subdivided into a symmetrical array of parasagittal stripes. The most extensively studied compartmentation antigen is zebrin II/aldolase c, which is expressed by a subset of Purkinje cells forming parasagittal stripes. Stripe phenotypes are specified early in cerebellar development, in part through the action of early B-cell factor 2 (Ebf2), a member of the atypical helix-loop-helix transcription factor family Collier/Olf1/EBF. In the murine cerebellum, Ebf2 expression is restricted to the zebrin II-immunonegative (zebrin II-) Purkinje cell population. We have identified multiple cerebellar defects in the Ebf2 null mouse involving a combination of selective Purkinje cell death and ectopic expression of multiple genes normally restricted to the zebrin II- subset. The nature of the cerebellar defect in the Ebf2 null is different in each transverse zone. In contrast to the ectopic expression of genes characteristic of the zebrin II+ Purkinje cell phenotype, phospholipase Cbeta4 expression, restricted to zebrin II- Purkinje cells in control mice, is well maintained, and the normal number of stripes is present. Taken together, these data suggest that Ebf2 regulates the expression of genes associated with the zebrin II+ Purkinje cell phenotype and that the zebrin II- Purkinje cell subtype is specified independently.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cerebelo/citología , Cerebelo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Células de Purkinje/metabolismo , Animales , Expresión Génica , Regulación de la Expresión Génica , Inmunohistoquímica , Ratones , Ratones Noqueados , Fenotipo , Células de Purkinje/citologíaRESUMEN
Cyclin-dependent kinase 5 (Cdk5) activity is required for CNS development. The Cdk5 activator, p35, is well characterized but its isoform, p39, has been less studied. Previously, p39 mRNA expression in rat brain was shown to peak at 3 weeks postnatal, and the level remains high in the adult cerebellum [Neurosci Res 28 (1997) 355]. However, p39 protein expression and specific localization in the cerebellum, where p39 mRNA level significantly exceeds that of p35, have not been examined. Here, we explored the specific cerebellar localization of the p39 protein in the developing and adult mice. Adult cerebellar Purkinje cell somata and dendritic arbors were strongly positive for p39 but only rare and barely detectable p39 was observed in Purkinje cell axons. Cdk5 also localized in Purkinje cell somata and dendrites of the adult cerebellum, but p35 localized only in Purkinje cell somata, further suggesting a functional difference between p35 and p39. During development, cerebellar p39 was first noted at P10. Primary cultures of a developing cerebellum also showed strong p39 immunoreactivity in Purkinje cell somata and dendrites, but weak p39 immunoreactivity in Purkinje cell axons. Starting from P10, p39 was observed in a subset of Purkinje cells that form parasagittal bands throughout the vermis and hemispheres. These bands were bilaterally symmetrical and continuous from one lobule to another. Conversely, Cdk5 and p35 showed a uniform staining pattern. The pattern of p39 closely resembled that of zebrin II/aldolase C, suggesting that p39 may play a role in the adult cerebellum rather than in pattern development. This premise is consistent with the normal pattern of zebrin II/aldolase C zones and stripes in mutant p39-/- mice. The alternating p39 parasagittal band pattern may reflect a role for p39 or Cdk5/p39 in the functional compartmentation of the cerebellum.
Asunto(s)
Cerebelo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Mapeo Encefálico , Cerebelo/citología , Cerebelo/embriología , Cerebelo/crecimiento & desarrollo , Quinasa 5 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/metabolismo , Inmunohistoquímica , Ratones , Ratones Noqueados , Células de Purkinje/metabolismoRESUMEN
Increasing the ectopic uterine motility is the major reason for primary dysmenorrhea. This motility is the basis for several symptoms including for pain is the main complaints of patients with primary dysmenorrhea. There are several mechanisms, which initiate dysmenorrhea. Therefore, different compounds can be employed to control its symptoms. In long-term therapy, combination of oestrogens and progestins may be useful. In short-term therapy, dysmenorrhea sometimes non-steroidal anti-inflammatory drugs (NSAIDs) are used. Most of NSAIDs in long-term therapy show severe adverse effects. In an attempt to find agents with less adverse effect the fennel essential oil (FEO) was chosen for this investigation. In this article, effects of FEO on the uterine contraction and estimation of LD(50) in rat were described. For assessment of pharmacological effects on the isolated rat uterus, oxytocin (0.1, 1 and 10 mu/ml) and prostaglandin E(2) (PGE(2)) (5x10(-5) M) were employed to induce muscle contraction. Administration of different doses of FEO reduced the intensity of oxytocin and PGE(2) induced contractions significantly (25 and 50 microg/ml for oxytocin and 10 and 20 microg/ml PGE(2), respectively). FEO also reduced the frequency of contractions induced by PGE(2) but not with oxytocin. LD(50) of FEO was obtained in the female rats by using moving average method. The estimated LD(50) was 1326 mg/kg. No obvious damage was observed in the vital organs of the dead animals.