RESUMEN
Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors of cytochrome c release from mitochondria. Drugs effective at the level of purified mitochondria were evaluated in a cellular model of HD. As proof of principle, one drug was chosen for in depth evaluation in vitro and a transgenic mouse model of HD. Our findings demonstrate the utility of mitochondrial screening to identify inhibitors of cell death and provide further support for the important functional role of cytochrome c release in HD. Given that many of these compounds have been approved by the Food and Drug Administration for clinical usage and cross the blood-brain barrier, these drugs may lead to trials in patients.
Asunto(s)
Encéfalo/efectos de los fármacos , Citocromos c/antagonistas & inhibidores , Enfermedad de Huntington/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Línea Celular Transformada , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/fisiopatología , Longevidad/efectos de los fármacos , Longevidad/fisiología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Metazolamida/farmacología , Metazolamida/uso terapéutico , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Resultado del TratamientoRESUMEN
Harnessing the regenerative potential of the central nervous system to repopulate depleted cellular populations from endogenous stem cells would be a novel approach for the treatment of neurological diseases resulting from cell death. Consequently, understanding if and how the central nervous system is capable of such regeneration would determine if such an approach is feasible. In this report, we provide evidence of widespread regenerative response in the spinal cord of amyotrophic lateral sclerosis transgenic mice. However, this regenerative response appears to be largely unproductive. We demonstrate that there is significantly increased gliogenesis, but an absence of convincing neurogenesis. The fact that the neurodegenerative process stimulates a regenerative response suggests that the adult spinal cord has at least limited ability for regeneration. Further studies will determine if this endogenous regenerative process can be enhanced and directed so as to slow or even reverse the natural progression of this devastating disease.