Systemic L-Buthionine -S-R-Sulfoximine Treatment Increases Plasma NGF and Upregulates L-cys/L-cys2 Transporter and γ-Glutamylcysteine Ligase mRNAs Through the NGF/TrkA/Akt/Nrf2 Pathway in the Striatum

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-cys 2 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.

N‑acetylcysteine inhibits atherosclerosis by correcting glutathione‑dependent methylglyoxal elimination and dicarbonyl/oxidative stress in the aorta of diabetic mice

“…3A ). BSO is an inhibitor of GSH ( 39 ). In vitro , NAC significantly reduced MG-induced ROS elevation compared with that in the MG group.…”

Early Neurotoxic Effects of Inorganic Arsenic Modulate Cortical GSH Levels Associated With the Activation of the Nrf2 and NFκB Pathways, Expression of Amino Acid Transporters and NMDA Receptors and the Production of Hydrogen Sulfide

“…Valdovinos-Flores and Gonsebatt (2013) observed significant transcription of ngfb at 2 h after a 14-mg/kg iAs i.p. injection, which was associated with the activation of the TrkA/Akt/NFκB signaling pathway in the liver but not in the striatum of mice (Valdovinos-Flores et al, 2019). However, systemic activation of this pathway could induce GSH synthesis in other brain regions such as the cortex and cerebellum at 24 h and 9 days ( Figures 1C,D).…”

Nerve growth factor enhances the therapeutic effect of mesenchymal stem cells on diabetic periodontitis

“…The in vivo experiments of the present study demonstrated that NGF was able to inhibit the conversion of MSCs to the proinflammatory type in diabetes and further decreased the infiltration of T cells and macrophages in periodontal tissues. TrkA is the major high-affinity receptor of NGF and has an irreplaceable role in the growth and development of the nervous system and the maintenance of neuronal characteristics (29). The combination of NGF and TrkA may further activate the MAPK signaling pathway and promote stem cell proliferation and differentiation (30,31).…”