mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats

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, micro...

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Published in:Canadian journal of physiology and pharmacology 2021-09, Vol.99 (9), p.921-934
Main Authors: Guden, Demet Sinem, Temiz-Resitoglu, Meryem, Senol, Sefika Pinar, Kibar, Deniz, Yilmaz, Sakir Necat, Tunctan, Bahar, Malik, Kafait U, Sahan-Firat, Seyhan
Format: Article
Language:English
Subjects:
Animals
apoptose
Apoptosis
Attention
Bcl-2 protein
Bcl-x protein
Care and treatment
Caspase-3
Hypoxia-Inducible Factor 1, alpha Subunit - physiology
Hypoxia-inducible factor 1a
I-kappa B Proteins - physiology
IL-1β
Inflammation
Inflammation - drug therapy
Kidneys
Kinases
Lipopolysaccharides
Lymphocytes B
Male
microglia
Microglia - drug effects
microglie
mTOR
Nervous system diseases
neuroinflammation
Neuroinflammatory Diseases - drug therapy
NF-κB protein
Nitric-oxide synthase
Nitrites
Oxidative stress
Oxidative Stress - drug effects
Physiological aspects
Rapamycin
Rats
Rats, Wistar
Ribosomal protein S6
Sepsis
Signal transduction
Sirolimus - pharmacology
stress oxydatif
TOR protein
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - physiology
Transcription Factor RelA - physiology
Tumor necrosis factor-α
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Summary: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-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) 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-κB p65 activity by increasing degradation of IκB-α in parallel with HIF-1α expression increased by LPS in the kidney, heart, lung, and brain tissues. Rapamycin attenuated the increment in the expression of tumor necrosis factor-α and interleukin-1β, 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 IκB-α/NF-κB/HIF-1α signaling pathway.
ISSN:0008-4212
1205-7541
DOI:10.1139/cjpp-2020-0487