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1.
J Clin Invest ; 119(8): 2291-303, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19620781

RESUMEN

The anorexigenic neuromodulator alpha-melanocyte-stimulating hormone (alpha-MSH; referred to here as alpha-MSH1-13) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of alpha-MSH1-13 maturation and inactivation is incompletely understood. Here we have provided insight into alpha-MSH1-13 inactivation through the generation and analysis of a subcongenic mouse strain with reduced body fat compared with controls. Using positional cloning, we identified a maximum of 6 coding genes, including that encoding prolylcarboxypeptidase (PRCP), in the donor region. Real-time PCR revealed a marked genotype effect on Prcp mRNA expression in brain tissue. Biochemical studies using recombinant PRCP demonstrated that PRCP removes the C-terminal amino acid of alpha-MSH1-13, producing alpha-MSH1-12, which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where alpha-MSH1-13 is released from axon terminals. The inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in both wild-type and obese mice. Furthermore, Prcp-null mice had elevated levels of alpha-MSH1-13 in the hypothalamus and were leaner and shorter than the wild-type controls on a regular chow diet; they were also resistant to high-fat diet-induced obesity. Our results suggest that PRCP is an important component of melanocortin signaling and weight maintenance via control of active alpha-MSH1-13 levels.


Asunto(s)
Carboxipeptidasas/fisiología , Ingestión de Alimentos , alfa-MSH/antagonistas & inhibidores , Animales , Carboxipeptidasas/antagonistas & inhibidores , Carboxipeptidasas/genética , Ingestión de Alimentos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Hipotálamo/metabolismo , Masculino , Hormonas Estimuladoras de los Melanocitos/metabolismo , Hormonas Estimuladoras de los Melanocitos/farmacología , Ratones , Ratones Endogámicos BALB C , Obesidad/etiología , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Reacción en Cadena de la Polimerasa , Pirimidinas/farmacología , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores de Melanocortina/fisiología , alfa-MSH/fisiología
2.
Neuropsychopharmacology ; 33(12): 2922-33, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18322467

RESUMEN

Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some individuals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.


Asunto(s)
Benzodiazepinas/antagonistas & inhibidores , Hiperglucemia/tratamiento farmacológico , Hiperfagia/tratamiento farmacológico , Isoxazoles/farmacología , Aumento de Peso/efectos de los fármacos , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Regulación del Apetito/efectos de los fármacos , Regulación del Apetito/fisiología , Benzodiazepinas/efectos adversos , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/fisiopatología , Femenino , Hiperglucemia/inducido químicamente , Hiperglucemia/fisiopatología , Hiperfagia/inducido químicamente , Hiperfagia/fisiopatología , Área Hipotalámica Lateral/efectos de los fármacos , Área Hipotalámica Lateral/metabolismo , Área Hipotalámica Lateral/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isoxazoles/uso terapéutico , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuropéptidos/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiopatología , Obesidad/inducido químicamente , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Olanzapina , Orexinas , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/antagonistas & inhibidores , Resultado del Tratamiento , Aumento de Peso/fisiología , Zonisamida
3.
Nat Med ; 11(9): 966-72, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16086023

RESUMEN

Demyelination is the hallmark of numerous neurodegenerative conditions, including multiple sclerosis. Oligodendrocyte progenitors (OPCs), which normally mature into myelin-forming oligodendrocytes, are typically present around demyelinated lesions but do not remyelinate affected axons. Here, we find that the glycosaminoglycan hyaluronan accumulates in demyelinated lesions from individuals with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. A high molecular weight (HMW) form of hyaluronan synthesized by astrocytes accumulates in chronic demyelinated lesions. This form of hyaluronan inhibits remyelination after lysolecithin-induced white matter demyelination. OPCs accrue and do not mature into myelin-forming cells in demyelinating lesions where HMW hyaluronan is present. Furthermore, the addition of HMW hyaluronan to OPC cultures reversibly inhibits progenitor-cell maturation, whereas degrading hyaluronan in astrocyte-OPC cocultures promotes oligodendrocyte maturation. HMW hyaluronan may therefore contribute substantially to remyelination failure by preventing the maturation of OPCs that are recruited to demyelinating lesions.


Asunto(s)
Astrocitos/fisiología , Enfermedades Desmielinizantes/fisiopatología , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/metabolismo , Oligodendroglía/fisiología , Animales , Encefalomielitis Autoinmune Experimental/fisiopatología , Humanos , Ratones , Esclerosis Múltiple/fisiopatología , Células Madre/fisiología
4.
Glia ; 47(4): 335-45, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15293231

RESUMEN

The CD44 transmembrane glycoprotein family has been implicated in cell-cell adhesion and cell signaling in response to components of the extracellular matrix but its role in the nervous system is not understood. CD44 proteins are elevated in Schwann cells and oligodendrocytes following nervous system insults, in inflammatory demyelinating lesions, and in tumors. Here, we tested the hypothesis that elevated CD44 expression influences Schwann cell and oligodendrocyte functions by generating transgenic mice that express CD44 under the control of the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) promoter. These mice failed to develop peripheral nerve or CNS tumors. However, they did develop severe tremors that were associated with CNS dysmyelination and progressive demyelination. Loss of CNS myelin was not due to alterations in early oligodendrocyte precursor differentiation, proliferation, or survival. Myelination in the PNS appeared normal. In no instance was there any evidence of an inflammatory response that could account for the loss of CNS myelin. These findings suggest that CNPase-CD44 mice are a novel model for noninflammatory progressive demyelinating disease and support a potential role for CD44 proteins expressed by glial cells in promoting demyelination.


Asunto(s)
Enfermedades Desmielinizantes/fisiopatología , Receptores de Hialuranos/genética , Neuritis/fisiopatología , Oligodendroglía/fisiología , Animales , Ataxia/inmunología , Ataxia/patología , Ataxia/fisiopatología , División Celular/inmunología , Supervivencia Celular/inmunología , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Expresión Génica/inmunología , Gliosis/inmunología , Gliosis/patología , Gliosis/fisiopatología , Receptores de Hialuranos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuritis/inmunología , Neuritis/patología , Oligodendroglía/citología , Células de Schwann/patología , Células de Schwann/fisiología , Temblor/inmunología , Temblor/patología , Temblor/fisiopatología
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