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1.
J Neuroinflammation ; 14(1): 25, 2017 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-28143498

RESUMEN

BACKGROUND: The mammalian target of rapamycin (mTOR) is a kinase involved in a variety of physiological and pathological functions. However, the exact role of mTOR in excitotoxicity is poorly understood. Here, we investigated the effects of mTOR inhibition with rapamycin against neurodegeneration, and motor impairment, as well as inflammatory profile caused by an excitotoxic stimulus. METHODS: A single and unilateral striatal injection of quinolinic acid (QA) was used to induce excitotoxicity in mice. Rapamycin (250 nL of 0.2, 2, or 20 µM; intrastriatal route) was administered 15 min before QA injection. Forty-eight hours after QA administration, rotarod test was performed to evaluate motor coordination and balance. Fluoro-Jade C, Iba-1, and GFAP staining were used to evaluate neuronal cell death, microglia morphology, and astrocytes density, respectively, at this time point. Levels of cytokines and neurotrophic factors were measured by ELISA and Cytometric Bead Array 8 h after QA injection. Striatal synaptosomes were used to evaluate the release of glutamate. RESULTS: We first demonstrated that rapamycin prevented the motor impairment induced by QA. Moreover, mTOR inhibition also reduced the neurodegeneration and the production of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α induced by excitotoxic stimulus. The lowest dose of rapamycin also increased the production of IL-10 and prevented the reduction of astrocyte density induced by QA. By using an in vitro approach, we demonstrated that rapamycin differently alters the release of glutamate from striatal synaptosomes induced by QA, reducing or enhancing the release of this neurotransmitter at low or high concentrations, respectively. CONCLUSION: Taken together, these data demonstrated a protective effect of rapamycin against an excitotoxic stimulus. Therefore, this study provides new evidence of the detrimental role of mTOR in neurodegeneration, which might represent an important target for the treatment of neurodegenerative diseases.


Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Ácido Quinolínico/toxicidad , Sirolimus/farmacología , Sirolimus/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Cuerpo Estriado/fisiología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ácido Glutámico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/etiología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Neuroglía/efectos de los fármacos , Neuroglía/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/complicaciones , Equilibrio Postural/efectos de los fármacos , Cloruro de Potasio/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Sinaptosomas/ultraestructura
2.
Exp Neurol ; 267: 123-34, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25749189

RESUMEN

Phosphatidylinositol 3-kinase (PI3K) is an enzyme involved in different pathophysiological processes, including neurological disorders. However, its role in seizures and postictal outcomes is still not fully understood. We investigated the role of PI3Kγ on seizures, production of neurotrophic and inflammatory mediators, expression of a marker for microglia, neuronal death and hippocampal neurogenesis in mice (WT and PI3Kγ(-/-)) subjected to intrahippocampal microinjection of pilocarpine. PI3Kγ(-/-) mice presented a more severe status epilepticus (SE) than WT mice. In hippocampal synaptosomes, genetic or pharmacological blockade of PI3Kγ enhanced the release of glutamate and the cytosolic calcium concentration induced by KCl. There was an enhanced neuronal death and a decrease in the doublecortin positive cells in the dentate gyrus of PI3Kγ(-/-) animals after the induction of SE. Levels of BDNF were significantly increased in the hippocampus of WT and PI3Kγ(-/-) mice, although in the prefrontal cortex, only PI3Kγ(-/-) animals showed significant increase in the levels of this neurotrophic factor. Pilocarpine increased hippocampal microglial immunolabeling in both groups, albeit in the prelimbic, medial and motor regions of the prefrontal cortex this increase was observed only in PI3Kγ(-/-) mice. Regarding the levels of inflammatory mediators, pilocarpine injection increased interleukin (IL) 6 in the hippocampus of WT and PI3Kγ(-/-) animals and in the prefrontal cortex of PI3Kγ(-/-) animals 24h after the stimulus. Levels of TNFα were enhanced in the hippocampus and prefrontal cortex of only PI3Kγ(-/-) mice at this time point. On the other hand, PI3Kγ deletion impaired the increase in IL-10 in the hippocampus induced by pilocarpine. In conclusion, the lack of PI3Kγ revealed a deleterious effect in an animal model of convulsions induced by pilocarpine, suggesting that this enzyme may play a protective role in seizures and pathological outcomes associated with this condition.


Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ib/deficiencia , Hipocampo/efectos de los fármacos , Agonistas Muscarínicos/toxicidad , Pilocarpina/toxicidad , Convulsiones/inducido químicamente , Convulsiones/genética , Animales , Calcio/metabolismo , Proteínas de Unión al Calcio/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteínas de Dominio Doblecortina , Inhibidores Enzimáticos/uso terapéutico , Ácido Glutámico/metabolismo , Hipocampo/ultraestructura , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/patología , Quinoxalinas/uso terapéutico , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/genética , Convulsiones/tratamiento farmacológico , Sinaptosomas/metabolismo , Sinaptosomas/patología , Tiazolidinedionas/uso terapéutico , Factores de Tiempo
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