PMID- 26218952
OWN - NLM
STAT- MEDLINE
DCOM- 20160224
LR  - 20181202
IS  - 2150-1149 (Electronic)
IS  - 1533-3159 (Linking)
VI  - 18
IP  - 4
DP  - 2015 Jul-Aug
TI  - Tanshinone IIA Attenuates Chronic Pancreatitis-Induced Pain in Rats via 
      Downregulation of HMGB1 and TRL4 Expression in the Spinal Cord.
PG  - E615-28
AB  - BACKGROUND: Chronic pancreatitis (CP) is a long-standing inflammation of the 
      exocrine pancreas, which typically results in severe and constant abdominal pain. 
      Previous studies on the mechanisms underlying CP-induced pain have primarily 
      focused on the peripheral nociceptive system. A role for a central mechanism in 
      the mediation or modulation of abdominal pain is largely unknown. Tanshinone IIA 
      (TSN IIA), an active component of the traditional Chinese medicine Danshen, 
      exhibits anti-inflammatory properties via downregulation of the expression of 
      high-mobility group protein B1 (HMGB1), a late proinflammatory cytokine. HMGB1 
      binds and activates toll-like receptor 4 (TLR4) to induce spinal astrocyte 
      activation and proinflammatory cytokine release in neuropathic pain. OBJECTIVE: 
      In this study, we investigated the effect of TSN IIA on pain responses in rats 
      with trinitrobenzene sulfonic acid (TNBS)-induced CP. The roles of central 
      mechanisms in the mediation or modulation of CP were also investigated. STUDY 
      DESIGN: A randomized, double-blind, placebo-controlled animal trial. METHODS: CP 
      was induced in rats by intrapancreatic infusion of trinitrobenzene sulfonic acid 
      (TNBS). Pancreatic histopathological changes were characterized with 
      semi-quantitative scores. The abdomen nociceptive behaviors were assessed with 
      von Frey filaments. The effects of intraperitoneally administered TSN IIA on 
      CP-induced mechanical allodynia were tested. The spinal protein expression of 
      HMGB1 was determined by western blot. The spinal mRNA and protein expression of 
      proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6 were determined by RT-PCR and 
      western blot, respectively. The spinal expression of the HMGB1 receptor TRL4 and 
      the astrocyte activation marker glial fibrillary acidic protein (GFAP) were 
      determined by western blot or immunohistological staining after intraperitoneal 
      injection of TSN IIA or intrathecal administration of a neutralizing anti-HMGB1 
      antibody. RESULTS: TNBS infusion resulted in pancreatic histopathological changes 
      of chronic pancreatitis and mechanical allodynia in rats. TSN IIA significantly 
      attenuated TNBS-induced mechanical allodynia in a dose-dependent manner. TNBS 
      significantly increased the spinal expression of HMGB1 and proinflammatory 
      cytokines IL-1beta, TNF-alpha, and IL-6. These TNBS-induced changes were significantly 
      inhibited by TSN IIA in a dose-dependent manner. Furthermore, TSN IIA, but not 
      the neutralizing anti-HMGB1 antibody, significantly inhibited TNBS-induced spinal 
      TLR4 and GFAP expression. LIMITATIONS: In addition to TLR4, HMGB1 can also bind 
      to toll-like receptor-2 (TLR2) and the receptor for advanced glycation end 
      products (RAGE). Additional studies are warranted to ascertain whether HMGB1 
      contributes to CP-induced pain through activation of these receptors. 
      CONCLUSIONS: Our results suggest that spinal HMGB1 contributes to the development 
      of CP-induced pain and can potentially be a therapeutic target. TSN IIA 
      attenuates CP-induced pain via downregulation of spinal HMGB1 and TRL4 
      expression. Therefore, TSN IIA may be a potential anti-nociceptive drug for the 
      treatment of CP-induced pain.
FAU - Wang, Ye-song
AU  - Wang YS
FAU - Li, Yuan-yuan
AU  - Li YY
FAU - Wang, Li-hua
AU  - Wang LH
FAU - Kang, Ying
AU  - Kang Y
FAU - Zhang, Jie
AU  - Zhang J
FAU - Liu, Zi-quan
AU  - Liu ZQ
FAU - Wang, Kun
AU  - Wang K
FAU - Kaye, Alan David
AU  - Kaye AD
FAU - Chen, Lei
AU  - Chen L
AD  - Department of Intensive Care Unit, Second Affiliated Hospital, School of Medcine, 
      Zhejiang University-Hangzhou 310009, Zhejiang, China; Neurointensive care unit, 
      Second Affiliated Hospital, School of Medcine, Zhejiang University-Hangzhou 
      310009, Zhejiang.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Pain Physician
JT  - Pain physician
JID - 100954394
RN  - 0 (Antibodies, Blocking)
RN  - 0 (Benzofurans)
RN  - 0 (Cytokines)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (HMGB1 Protein)
RN  - 0 (Hbp1 protein, rat)
RN  - 0 (Tlr4 protein, rat)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (tashinone IIA)
RN  - 8T3HQG2ZC4 (Trinitrobenzenesulfonic Acid)
SB  - IM
MH  - Animals
MH  - Antibodies, Blocking/administration & dosage/therapeutic use
MH  - Benzofurans/administration & dosage/*therapeutic use
MH  - Cytokines/metabolism
MH  - Down-Regulation/drug effects
MH  - Glial Fibrillary Acidic Protein/biosynthesis/genetics
MH  - HMGB1 Protein/*biosynthesis/genetics
MH  - Hyperalgesia/drug therapy/etiology
MH  - Injections, Intraperitoneal
MH  - Injections, Spinal
MH  - Neuralgia/drug therapy/genetics
MH  - Pain/*drug therapy/*etiology
MH  - Pain Measurement
MH  - Pancreatitis, Chronic/chemically induced/*complications/pathology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Toll-Like Receptor 4/*biosynthesis/genetics
MH  - Trinitrobenzenesulfonic Acid
EDAT- 2015/07/29 06:00
MHDA- 2016/02/26 06:00
CRDT- 2015/07/29 06:00
PHST- 2015/07/29 06:00 [entrez]
PHST- 2015/07/29 06:00 [pubmed]
PHST- 2016/02/26 06:00 [medline]
PST - ppublish
SO  - Pain Physician. 2015 Jul-Aug;18(4):E615-28.