期刊
MOLECULAR NEUROBIOLOGY
卷 58, 期 4, 页码 1345-1371出版社
SPRINGER
DOI: 10.1007/s12035-020-02188-7
关键词
Amyotrophic lateral sclerosis; Motor neuron; SOD1(G93A); Oxidative stress; Neuroinflammation; Nicotinamide riboside; Pterostilbene; Antioxidant defenses; Glutathione; Sirtuins
资金
- University of Valencia (Spain) [OTR2017-18255INVES, OTR2018-19337INVES]
- Elysium Health Inc. (USA)
Research showed that the combination of nicotinamide riboside and pterostilbene significantly improved neuronal activity and coordination in ALS patients and transgenic mice. These molecules not only prolonged survival in mice but also reduced inflammation associated with ALS progression.
Oxidative stress-induced damage is a major mechanism in the pathophysiology of amyotrophic lateral sclerosis (ALS). A recent human clinical trial showed that the combination of nicotinamide riboside (NR) and pterostilbene (PT), molecules with potential to interfere in that mechanism, was efficacious in ALS patients. We examined the effect of these molecules in SOD1(G93A) transgenic mice, a well-stablished model of ALS. Assessment of neuromotor activity and coordination was correlated with histopathology, and measurement of proinflammatory cytokines in the cerebrospinal fluid. Cell death, Nrf2- and redox-dependent enzymes and metabolites, and sirtuin activities were studied in isolated motor neurons. NR and PT increased survival and ameliorated ALS-associated loss of neuromotor functions in SOD1(G93A) transgenic mice. NR and PT also decreased the microgliosis and astrogliosis associated with ALS progression. Increased levels of proinflammatory cytokines were observed in the cerebrospinal fluid of mice and humans with ALS. NR and PT ameliorated TNF alpha-induced oxidative stress and motor neuron death in vitro. Our results support the involvement of oxidative stress, specific Nrf2-dependent antioxidant defenses, and sirtuins in the pathophysiology of ALS. NR and PT interfere with the mechanisms leading to the release of proapoptotic molecular signals by mitochondria, and also promote mitophagy.
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