PMID- 30325723
OWN - NLM
STAT- MEDLINE
DCOM- 20200114
LR  - 20211204
IS  - 1743-1328 (Electronic)
IS  - 0161-6412 (Linking)
VI  - 41
IP  - 1
DP  - 2019 Jan
TI  - Rapamycin alleviates proinflammatory cytokines and nociceptive behavior induced 
      by chemotherapeutic paclitaxel.
PG  - 52-59
LID - 10.1080/01616412.2018.1531199 [doi]
AB  - Background/Aims: Paclitaxel is largely used as a chemotherapeutic agent for the 
      treatment of several types of cancers. However, one of the significant limiting 
      complications of paclitaxel is painful peripheral neuropathy during its therapy. 
      The purposes of this study were to examine (1) the effects of blocking mammalian 
      target of rapamycin (mTOR) on mechanical and thermal hypersensitivity evoked by 
      paclitaxel; and (2) the underlying mechanisms responsible for the role of mTOR in 
      regulating paclitaxel-induced neuropathic pain. Methods: Behavioral test was 
      performed to determine mechanical and thermal sensitivity in rats. ELISA was used 
      to examine the levels of proinflammatory cytokines (PICs including IL-1beta, IL-6, 
      and TNF-alpha) and substance P and calcitonin gene-related peptide (CGRP) in the 
      dorsal root ganglion (DGR); and Western blot analysis was used to examine 
      expression of mTOR signal pathway. Results: Paclitaxel increased mechanical and 
      thermal sensitivity as compared with vehicle control animals (P < 0.05 vs. 
      controls). Paclitaxel also amplified the expression of p-mTOR, mTOR-mediated 
      phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4E-binding protein 
      1 (p-4E-BP1) in the DRG. Blocking mTOR using rapamycin attenuated peripheral 
      painful neuropathy observed in paclitaxel rats (P < 0.05 vs. without rapamycin). 
      This inhibitory effect was accompanied with decreases of IL-1beta, IL-6, and TNF-alpha 
      as well as substance P and CGRP. In addition, inhibition of phosphatidylinositide 
      3-kinase (p-PI3K) attenuated expression of p-mTOR and PICs/substance P/CGRP in 
      paclitaxel rats and this further attenuated mechanical and thermal 
      hypersensitivity. Conclusions: The data revealed specific signaling pathways 
      leading to paclitaxel-induced peripheral neuropathic pain, including the 
      activation of PI3K-mTOR, PIC signal, and substance P and CGRP. Inhibition of 
      these pathways alleviates neuropathic pain. Targeting one or more of these 
      molecular mediators may present new opportunities for treatment and management of 
      neuropathic pain observed during chemotherapeutic application of paclitaxel.
FAU - Zhang, Xiaoli
AU  - Zhang X
AD  - a Department of Pulmonary Medicine , The First Hospital (Eastern Division) of 
      Jilin University , Changchun , China.
FAU - Jiang, Nan
AU  - Jiang N
AD  - a Department of Pulmonary Medicine , The First Hospital (Eastern Division) of 
      Jilin University , Changchun , China.
FAU - Li, Jing
AU  - Li J
AD  - b Department of Radiology , The First Hospital (Eastern Division) of Jilin 
      University , Changchun , China.
FAU - Zhang, Dongyan
AU  - Zhang D
AD  - c Department of Ophthalmology , The First Hospital of Jilin University , 
      Changchun , China.
FAU - Lv, Xiaohong
AU  - Lv X
AD  - a Department of Pulmonary Medicine , The First Hospital (Eastern Division) of 
      Jilin University , Changchun , China.
LA  - eng
PT  - Journal Article
DEP - 20181016
PL  - England
TA  - Neurol Res
JT  - Neurological research
JID - 7905298
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Cytokines)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - P88XT4IS4D (Paclitaxel)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Antineoplastic Agents, Phytogenic/*adverse effects
MH  - Cytokines/*metabolism
MH  - Hyperalgesia/drug therapy/etiology/metabolism
MH  - Inflammation/drug therapy/etiology/metabolism
MH  - Male
MH  - Nociceptive Pain/*drug therapy/etiology/metabolism
MH  - Paclitaxel/*adverse effects
MH  - Rats, Sprague-Dawley
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - Paclitaxel
OT  - mTOR
OT  - neuropathic pain
OT  - proinflammation
OT  - rapamycin
EDAT- 2018/10/17 06:00
MHDA- 2020/01/15 06:00
CRDT- 2018/10/17 06:00
PHST- 2018/10/17 06:00 [pubmed]
PHST- 2020/01/15 06:00 [medline]
PHST- 2018/10/17 06:00 [entrez]
AID - 10.1080/01616412.2018.1531199 [doi]
PST - ppublish
SO  - Neurol Res. 2019 Jan;41(1):52-59. doi: 10.1080/01616412.2018.1531199. Epub 2018 
      Oct 16.