RESUMO
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.
Assuntos
Encéfalo/efeitos dos fármacos , Citocromos c/antagonistas & inibidores , Doença de Huntington/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/uso terapêutico , Caspases/efeitos dos fármacos , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Linhagem Celular Transformada , Citocromos c/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Longevidade/efeitos dos fármacos , Longevidade/fisiologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/fisiologia , Metazolamida/farmacologia , Metazolamida/uso terapêutico , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Resultado do TratamentoRESUMO
Essential tremor (ET) is the most prevalent tremor syndrome. It commonly affects the hands, head, voice, and other body parts. Appropriate management begins with correct diagnosis. Primidone and propranolol are the first-line medications for the treatment for ET, but several other medications may also provide benefit. In patients with medically refractory tremor, alternative therapies, including surgery or injections of botulinum toxin, may be considered.