The central nervous system (CNS) uses a significant amount of
oxygen for energy production. Decreased
oxygen supply due to impaired blood supply critically damages the CNS. As chronic hypoxic conditions have diverse effects via the excessive production of
reactive oxygen species, protection from hypoxic damage is important for cell survival. Recent studies have revealed that various markers of
hypoxia are altered in age-related
neurodegenerative diseases such as
amyotrophic lateral sclerosis (ALS), indicating the involvement of
hypoxia. However, therapeutic strategies targeting
hypoxia-induced pathways in ALS have not been developed yet. We previously screened small-molecule compounds that inhibit
hypoxia-induced cell death and identified
6-deoxyjacareubin. We hypothesized that the modulation of
hypoxia signaling by
6-deoxyjacareubin might protect motor neurons in ALS. Here, we show that
6-deoxyjacareubin indeed ameliorates neurodegeneration in a mouse model of familial ALS. Administration of
6-deoxyjacareubin to this familial ALS model significantly attenuated
disease progression and improved locomotor dysfunction. We also found that
6-deoxyjacareubin reduced motor neuron loss and glial activation. Our results indicate that
6-deoxyjacareubin might serve as a potential therapeutic tool for ALS. Moreover, these results suggest that modulation of
hypoxia signaling pathways provides a promising strategy to develop
therapies for other types of
neurodegenerative diseases also characterized by
hypoxia.