Systemic L-buthionine-S-R-sulfoximine administration modulates glutathione homeostasis via NGF/TrkA and mTOR signaling in the cerebellum

Garza-Lombó, Carla; Petrosyan, Pavel; Tapia-Rodríguez, Miguel; Valdovinos-Flores, Cesar; Gonsebatt, María E.

doi:10.1016/j.neuint.2018.10.007

Cited by 8 publications

(11 citation statements)

References 66 publications

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“…The response observed here was according to the previous report. Under the same exposure protocol, we observed the activation of the NGF/TrkA pathways in the cerebellum (Garza-Lombó et al, 2018).…”

Section: Resultsmentioning

confidence: 76%

“…We previously found that xct mRNA is upregulated in whole brain homogenates after GSH depletion (Limón-Pacheco et al, 2007), and more recently we have shown that EAAT3 protein levels are upregulated after the i.p. injection of BSO via the NGF/TrkA and mTOR signaling in the cerebellum (Garza-Lombó et al, 2018). Thus, we next examined the modulatory effects of BSO on the mRNA expression of CNS AA transporters that provide L-cys, such as lat1 and eaac1 , and L-cys 2 /glutamate, such as xct , in the striatum.…”

Section: Resultsmentioning

confidence: 99%

“…The systemic inhibition of GSH synthesis by L-buthionine-S-R-sulfoximine (BSO, Meister, 1995) in liver and kidneys or the exposure to a toxic metalloid such as arsenite, rose brain GSH pools in mice. Simultaneously, we observed an up-regulation of amino acid transporters, such as xCT and EAAT3 (Limón-Pacheco et al, 2007; Ramos-Chávez et al, 2015; Garza-Lombó et al, 2018), which were associated with a disruption of glutamate disposition and potentially leading to neurotoxicity (Nelson-Mora et al, 2018).…”

Section: Introductionmentioning

confidence: 91%

“…In the cerebellum, EAAT3 up-regulation and increased GSH levels were associated with an earlier activation of the NGF/TrkA and mTOR signaling pathways in neurons (Garza-Lombó et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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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

Valdovinos-Flores

Limón-Pacheco

León‐Rodríguez

et al. 2019

Front. Cell. Neurosci.

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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.

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Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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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

Valdovinos-Flores

Limón-Pacheco

León‐Rodríguez

et al. 2019

Front. Cell. Neurosci.

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“…Acute neurotoxic effects after oral doses include mild to severe encephalopathy, depending on the dose. Symptoms include confusion, hallucinations, reduced memory, and emotional lability (exaggerated changes in mood or affect; Garza-Lombó et al, 2018a,b, 2019. On the other hand, chronic exposure to iAs is associated with the development of peripheral neuropathies (Garza-Lombó et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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

Silva-Adaya

Ramos-Chávez

Petrosyan

et al. 2020

Front. Cell. Neurosci.

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Exposure to toxic metals and metalloids is an important cause of preventable diseases worldwide. Inorganic arsenic (iAs) affects several organs and tissues, causing neurobehavioral alterations in the central nervous system (CNS) that might lead to neurodegeneration. In this work, we wanted to explore the time-and dose-related changes on glutathione (GSH) levels in several regions of the CNS, such as the cortex, striatum, hippocampus, and cerebellum, to identify the initial cellular changes associated to GSH depletion due to iAs exposure. Mice received a single intraperitoneal injection containing 5 or 14 mg/kg sodium arsenite. Animals were killed at 2, 6, and 24 h. Significant depletion of GSH levels was observed in the cortex at 2 and 6 h, while on the striatum, hippocampus, or cerebellum regions, no significant changes were observed. GSH depletion in the cortex was associated with the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NFκB) pathways, which led to the upregulation of xCT, excitatory amino acid carrier 1 (EAAC1), glutamate/aspartate transporter (GLAST), and glial glutamate transporter 1 (GLT-1), and the activation of the transsulfuration pathways, which led to the overproduction of H 2 S in the cortex and increased levels of GSH in the cortex and cerebellum at 24 h. In the cortex, the N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B were also altered at 24 h. These early effects were not homogeneous among different brain regions and indicate early neurotoxic alterations in the cortex and cerebellum.

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The impact of glutathione metabolism in autism spectrum disorder

Bjørklund

Doşa

Maes

et al. 2021

Pharmacological Research

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Systemic L-buthionine-S-R-sulfoximine administration modulates glutathione homeostasis via NGF/TrkA and mTOR signaling in the cerebellum

Cited by 8 publications

References 66 publications

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

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

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

The impact of glutathione metabolism in autism spectrum disorder

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