PMID- 30300680
OWN - NLM
STAT- MEDLINE
DCOM- 20190913
LR  - 20211204
IS  - 1872-9754 (Electronic)
IS  - 0197-0186 (Linking)
VI  - 121
DP  - 2018 Dec
TI  - Systemic L-buthionine-S-R-sulfoximine administration modulates glutathione 
      homeostasis via NGF/TrkA and mTOR signaling in the cerebellum.
PG  - 8-18
LID - S0197-0186(18)30400-5 [pii]
LID - 10.1016/j.neuint.2018.10.007 [doi]
AB  - Glutathione (GSH) is an essential component of intracellular antioxidant systems 
      that plays a primordial role in the protection of cells against oxidative stress, 
      maintaining redox homeostasis and xenobiotic detoxification. GSH synthesis in the 
      brain is limited by the availability of cysteine and glutamate. Cystine, the 
      disulfide form of cysteine is transported into endothelial cells of the 
      blood-brain barrier (BBB) and astrocytes via the system x(c)(-), which is 
      composed of xCT and the heavy chain of 4F2 cell surface antigen (4F2hc). Cystine 
      is reduced inside the cells and the L-type amino acid transporter 1 (LAT1) 
      transports cysteine from the endothelial cells into the brain, cysteine is 
      transported into the neurons through the excitatory amino acid transporter 3 
      (EAAT3), also known as excitatory amino acid carrier 1 (EAAC1). The 
      mechanistic/mammalian target of rapamycin (mTOR) and neurotrophins can activate 
      signaling pathways that modulate amino acid transporters for GSH synthesis. The 
      present study found that systemic L-buthionine-S-R-sulfoximine (BSO) 
      administration selectively altered GSH homeostasis and EAAT3 levels in the mice 
      cerebellum. Intraperitoneal treatment of mice with 6 mmol/kg of BSO depleted GSH 
      and GSSG in the liver at 2 h of treatment. The cerebellum, but not other brain 
      regions, exhibited a redox response. The mTOR and the neuronal growth factor 
      (NGF)/tropomyosin receptor kinase A (TrkA) signaling pathways were activated and 
      lead to an increase in the protein levels of the EAAT3 transporter, which was 
      linked to an increase in the GSH/GSSG ratio and GSH concentration in the 
      cerebellum at 0.5 and 2 h, respectively. Therefore, the cerebellum responds to 
      peripheral GSH depletion via activation of the mTOR and NGF/TrkA pathways, which 
      increase the transport of cysteine for GSH synthesis.
CI  - Copyright (c) 2018. Published by Elsevier Ltd.
FAU - Garza-Lombo, Carla
AU  - Garza-Lombo C
AD  - Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de 
      Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, 
      04510, Mexico. Electronic address: carla.garza@gmail.com.
FAU - Petrosyan, Pavel
AU  - Petrosyan P
AD  - Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de 
      Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, 
      04510, Mexico. Electronic address: pavel@biomedicas.unam.mx.
FAU - Tapia-Rodriguez, Miguel
AU  - Tapia-Rodriguez M
AD  - Unidad de Microscopia, Instituto de Investigaciones Biomedicas, Universidad 
      Nacional Autonoma de Mexico, Mexico City, 04510, Mexico. Electronic address: 
      mtapia@biomedicas.unam.mx.
FAU - Valdovinos-Flores, Cesar
AU  - Valdovinos-Flores C
AD  - Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de 
      Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, 
      04510, Mexico. Electronic address: vinosvaldo@hotmail.com.
FAU - Gonsebatt, Maria E
AU  - Gonsebatt ME
AD  - Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de 
      Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, 
      04510, Mexico. Electronic address: margen@unam.mx.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181006
PL  - England
TA  - Neurochem Int
JT  - Neurochemistry international
JID - 8006959
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (NTRK1 protein, human)
RN  - 5072-26-4 (Buthionine Sulfoximine)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (Receptor, trkA)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Buthionine Sulfoximine/*administration & dosage
MH  - Cerebellum/drug effects/*metabolism
MH  - Enzyme Inhibitors/administration & dosage
MH  - Glutathione/antagonists & inhibitors/*metabolism
MH  - Homeostasis/drug effects/*physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Nerve Growth Factor/*metabolism
MH  - Receptor, trkA/*metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - TOR Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - Cerebellum
OT  - Cysteine transport
OT  - GSH
OT  - NGF
OT  - Redox
OT  - mTOR
EDAT- 2018/10/10 06:00
MHDA- 2019/09/14 06:00
CRDT- 2018/10/10 06:00
PHST- 2018/08/10 00:00 [received]
PHST- 2018/10/02 00:00 [revised]
PHST- 2018/10/03 00:00 [accepted]
PHST- 2018/10/10 06:00 [pubmed]
PHST- 2019/09/14 06:00 [medline]
PHST- 2018/10/10 06:00 [entrez]
AID - S0197-0186(18)30400-5 [pii]
AID - 10.1016/j.neuint.2018.10.007 [doi]
PST - ppublish
SO  - Neurochem Int. 2018 Dec;121:8-18. doi: 10.1016/j.neuint.2018.10.007. Epub 2018 
      Oct 6.