PMID- 33641344
OWN - NLM
STAT- MEDLINE
DCOM- 20220117
LR  - 20220117
IS  - 1205-7541 (Electronic)
IS  - 0008-4212 (Linking)
VI  - 99
IP  - 9
DP  - 2021 Sep
TI  - mTOR inhibition as a possible pharmacological target in the management of 
      systemic inflammatory response and associated neuroinflammation by 
      lipopolysaccharide challenge in rats.
PG  - 921-934
LID - 10.1139/cjpp-2020-0487 [doi]
AB  - Neuroinflammation plays a critical role during sepsis triggered by microglial 
      activation. Mammalian target of rapamycin (mTOR) has gained attraction in 
      neuroinflammation, however, the mechanism remains unclear. Our goal was to assess 
      the effects of mTOR inhibition by rapamycin on inflammation, microglial 
      activation, oxidative stress, and apoptosis associated with the changes in the 
      inhibitor-kappaB (IkappaB)-alpha/nuclear factor-kappaB (NF-kappaB)/hypoxia-inducible factor-1alpha 
      (HIF-1alpha) pathway activity following a systemic challenge with lipopolysaccharide 
      (LPS). Rats received saline (10 mL/kg), LPS (10 mg/kg), and (or) rapamycin 
      (1 mg/kg) intraperitoneally. Inhibition of mTOR by rapamycin blocked 
      phosphorylated form of ribosomal protein S6, NF-kappaB p65 activity by increasing 
      degradation of IkappaB-alpha in parallel with HIF-1alpha expression increased by LPS in the 
      kidney, heart, lung, and brain tissues. Rapamycin attenuated the increment in the 
      expression of tumor necrosis factor-alpha and interleukin-1beta, the inducible nitric 
      oxide synthase, gp91(phox), and p47(phox) in addition to nitrite levels elicited 
      by LPS in tissues or sera. Concomitantly, rapamycin treatment reduced microglial 
      activation, brain expression of caspase-3, and Bcl-2-associated X protein while 
      it increased expression of B cell lymphoma 2 induced by LPS. Overall, this study 
      supports the hypothesis that mTOR contributes to the detrimental effect of 
      LPS-induced systemic inflammatory response associated with neuroinflammation via 
      IkappaB-alpha/NF-kappaB/HIF-1alpha signaling pathway.
FAU - Guden, Demet Sinem
AU  - Guden DS
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
FAU - Temiz-Resitoglu, Meryem
AU  - Temiz-Resitoglu M
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
FAU - Senol, Sefika Pinar
AU  - Senol SP
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
FAU - Kibar, Deniz
AU  - Kibar D
AD  - Department of Histology and Embryology, Faculty of Medicine, Mersin University, 
      Mersin, Turkey.
FAU - Yilmaz, Sakir Necat
AU  - Yilmaz SN
AD  - Department of Histology and Embryology, Faculty of Medicine, Mersin University, 
      Mersin, Turkey.
FAU - Tunctan, Bahar
AU  - Tunctan B
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
FAU - Malik, Kafait U
AU  - Malik KU
AD  - Department of Pharmacology, College of Medicine, University of Tennessee, 
      Department of Pharmacology, College of Medicine, Memphis, TN, USA.
FAU - Sahan-Firat, Seyhan
AU  - Sahan-Firat S
AD  - Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 
      Turkey.
LA  - eng
PT  - Journal Article
DEP - 20210227
PL  - Canada
TA  - Can J Physiol Pharmacol
JT  - Canadian journal of physiology and pharmacology
JID - 0372712
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Transcription Factor RelA)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/physiology
MH  - I-kappa B Proteins/physiology
MH  - Inflammation/*drug therapy
MH  - Lipopolysaccharides
MH  - Male
MH  - Microglia/drug effects
MH  - Neuroinflammatory Diseases/*drug therapy
MH  - Oxidative Stress/drug effects
MH  - Rats
MH  - Rats, Wistar
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/physiology
MH  - Transcription Factor RelA/physiology
OTO - NOTNLM
OT  - apoptose
OT  - apoptosis
OT  - mTOR
OT  - microglia
OT  - microglie
OT  - neuroinflammation
OT  - oxidative stress
OT  - stress oxydatif
EDAT- 2021/03/02 06:00
MHDA- 2022/01/18 06:00
CRDT- 2021/03/01 05:23
PHST- 2021/03/02 06:00 [pubmed]
PHST- 2022/01/18 06:00 [medline]
PHST- 2021/03/01 05:23 [entrez]
AID - 10.1139/cjpp-2020-0487 [doi]
PST - ppublish
SO  - Can J Physiol Pharmacol. 2021 Sep;99(9):921-934. doi: 10.1139/cjpp-2020-0487. 
      Epub 2021 Feb 27.