RESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal and incurable neurodegenerative disorder. Motor neurone degeneration can be caused by genetic mutation but the exact etiology of the disease, particularly for sporadic illness, still remains unclear. Therapeutics which target known pathogenic mechanisms involved in ALS, such as protein aggregation, oxidative stress, apoptosis, inflammation, endoplasmic reticulum stress and mitochondria dysfunction, are currently being pursued in order to provide neuroprotection which may be able to slow down, or perhaps even halt, disease progression. This present review focuses on the compounds which have been recently evaluated using the SOD1 mouse model, the most widely used preclinical model for ALS research.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Superóxido Dismutase-1/genética , Esclerose Lateral Amiotrófica/genética , Animais , Produtos Biológicos/uso terapêutico , Modelos Animais de Doenças , Descoberta de Drogas , Humanos , CamundongosRESUMO
Cellular studies have been undertaken on a nonamer peptide nucleic acid (PNA) sequence, which binds to mRNA encoding superoxide dismutase 1, and a series of peptide nucleic acids conjugated to synthetic lipophilic vitamin analogs including a recently prepared menadione (vitamin K) analog. Reduction of both mutant superoxide dismutase 1 inclusion formation and endoplasmic reticulum stress, two of the key cellular pathological hallmarks in amyotrophic lateral sclerosis, by two of the prepared PNA oligomers is reported for the first time.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Nucleicos Peptídicos/farmacologia , Superóxido Dismutase/metabolismo , Vitaminas/farmacologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Células Cultivadas , Camundongos , Ácidos Nucleicos Peptídicos/síntese química , Ácidos Nucleicos Peptídicos/química , Superóxido Dismutase/deficiência , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Termodinâmica , Vitaminas/químicaRESUMO
To the N-terminus of a nonamer peptide nucleic acid sequence, H-GCACGACTT-NH2, was attached a number of lipophilic conjugate molecules including three synthetic tocopherol (vitamin E) analogues. Studies were then undertaken with complementary PNA and DNA sequences to explore the effects of the conjugates using the techniques of UV monitored melting curves and isothermal calorimetry. Duplex formation was observed when the benzopyran group of vitamin E was conjugated. However, in the presence of the phytyl chain of vitamin E, binding was found to be temperature dependent.
