Abstract
Glutathione (GSH) is the most abundant intracellular antioxidant. GSH depletion leads to oxidative stress and neuronal damage in the central nervous system (CNS). In mice, the acute systemic inhibition of GSH synthesis by L-buthionine-S-R-sulfoximine (BSO) triggers a protective response and a subsequent increase in the CNS GSH content. This response might be modulated by a peripheral increment of circulating nerve growth factor (NGF). NGF is an important activator of antioxidant pathways mediated by tropomyosin-related kinase receptor A (TrkA). Here, we report that peripheral administration of BSO increased plasma NGF levels. Additionally, BSO increased NGF levels and activated the NGF/TrkA/Akt pathway in striatal neurons. Moreover, the response in the striatum included an increased transcription of nrf2, gclm, lat1, eaac1, and xct, all of which are involved in antioxidant responses, and L-cys/L-cys2 and glutamate transporters. Using antibody against NGF confirmed that peripheral NGF activated the NGF/TrkA/Akt/Nrf2 pathway in the striatum and subsequently increased the transcription of gclm, nrf2, lat1, eaac1, and xct. These results provide evidence that the reduction of peripheral GSH pools increases peripheral NGF circulation that orchestrates a neuroprotective response in the CNS, at least in the striatum, through the NGF/TrkA/Akt/Nrf2 pathway.
Highlights
Reactive oxygen species (ROS) are products of aerobic metabolism
The experiments reported in this manuscript were conducted according to the guidelines stated in the Principles of Laboratory Animal Care (Institute for Laboratory Animal Research., 2011) and the Norma Oficial Mexicana de la Secretaría de Agricultura, Ganadería, Desarrollo Rural, Pesca y Alimentación (SAGARPA, México) Especificaciones técnicas para la nerve growth factor (NGF) Protein Levels Are Increased in the Plasma and Striatum, and NGF/tropomyosin-related kinase receptor A (TrkA) Pathway Is Activated in the Striatum After BSO Treatment Which Depletes Liver GSH
These results indicate that systemic treatment with BSO induces the synthesis of NGF by peripheral tissues, as well as the NGF and TrkA protein levels and TrkA phosphorylation in the striatum, possibly as a response to systemic oxidative stress induced by GSH depletion after BSO treatment (Table 2), suggesting that NGF is a redox sensor in both the peripheral tissues and striatum
Summary
Up to 2% of oxygen uptake is converted into ROS (Bridges et al, 2012) Some of these intracellular ROS activate cellular signals involved in the protection against oxidative stress, such as the synthesis of glutathione (GSH), thioredoxin (Trx-1) and antioxidant enzymes. Redox Changes Induce NGF organs contain specific antioxidant reservoirs, likely due to their different metabolic rates, which are reflected by their blood supply and oxygen consumption (Limón-Pacheco and Gonsebatt, 2009). These distinct features cause some organs, such as the brain, to be susceptible to oxidative injury. Aging as well as degenerative and neuropsychiatric diseases, such as Parkinson’s disease, Alzheimer’s disease, autism and schizophrenia, are associated with increased ROS production, the disruption of cellular GSH pools, and downregulation of GSHdependent enzymes (Ballatori et al, 2009; Johnson et al, 2012; Gu et al, 2015)
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