Tanshinone II A down-regulates HMGB1, RAGE, TLR4, NF-kappaB expression, ameliorates BBB permeability and endothelial cell function, and protects rat brains against focal ischemia.
Inflammatory damage plays an important role in cerebral ischemic pathogenesis. HMGB1-induced NF-kappaB activation pathway has been gaining recognition as a key contributor to the proinflammatory response. Tanshinone II A (Tan II A) has been proved to elicit a series of biologic effects through its antiinflammatory property. But the mechanism underlying is poorly understood. This study evaluated the Tan II A's protective role in cerebral ischemia and its potential mechanism. Male Sprague-Dawley rats were subjected to pMCAO. Experiment 1 was used to evaluate the longitudinal expression of HMGB1, RAGE and TLR4 and NF-kappaB in the cerebral ischemia. Experiment 2 was used to detect Tan II A's neuroprotection. At 24 h after pMCAO, neurologic deficit, brain water content and infarct size were measured. Immunohistochemistry, RT-PCR, Western blot and confocal microscope were used to analyze the expression of HMGB1, RAGE, TLR4 and NF-kappaB. Experiment 3 was used to detect Tan II A's influence on BBB. The expressions of HMGB1, TLR4, RAGE and NF-kappaB were up-regulated in ischemic brain. Compared with pMCAO group, the expressions of these factors significantly decreased in Tan II A-H group, the neurologic deficit, infarct volume and brain water content were alleviated (P<0.05) and claudin-5 was predominantly expressed in brain capillaries. Tan II A protected the brain from damage caused by pMCAO; this effect may be through down-regulation of HMGB1, RAGE and TLR4, NF-kappaB and up-regulation claudin-5 expression.
Wang
Lina
L
Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
Zhang
Xiangjian
X
Liu
Lingling
L
Cui
Lili
L
Yang
Rui
R
Li
Min
M
Du
Wei
W
D045784:Abietanes; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D062507:Claudin-5; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects*; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000187:drug effects; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000096:biosynthesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010616:Phenanthrenes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000187:drug effects
D045784:Abietanes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D062507:Claudin-5; C491510:Cldn5 protein, rat; D024243:HMGB1 Protein; D008565:Membrane Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010616:Phenanthrenes; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C021751:tanshinone