title: Tanshinone I selectively suppresses pro-inflammatory genes expression in activated microglia and prevents nigrostriatal dopaminergic neurodegeneration in a mouse model of Parkinson's disease.
abstract: BACKGROUND
  Radix Salviae Miltiorrhizae, known as Danshen, is a well-known traditional Chinese herb which has been used extensively for the treatment of various diseases, including cardiovascular and cerebrovascular disease and neurodegenerative diseases for thousands of years. Tanshinone I is one of major bioactive flavonoids of Radix Salviae Miltiorrhizae. Modulation of microglial over-reaction may represent a therapeutic target to alleviate the progression of neurodegenerative diseases. Here, we tested the effect of Tanshinone I on neuro-inflammation and whether it can provide neuroprotection through inhibition of neuro-inflammation.
  
  
  METHODS
  The effects of Tanshinone I on the production and/or mRNA expression of pro-inflammatory and anti-inflammatory factors in lipopolysaccharide(LPS)-induced BV-2 microglia cells were tested by Griess reaction, enzyme-linked immunosorbent assay (Elisa) or real time polymerase chain reaction. Activation of nuclear factor κ B (NF-κB) was measured by the nuclear translocation p65 and DNA binding activity. A model of Parkinson׳s disease was established by treatment of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6 mice. The effect of Tanshinone I on the behavioral changes, dopamine and its metabolites levels, expression of tyrosine hydroxylase (TH) and IBA-1, production of cytokines in the midbrain were investigated by the rotarod test, high-performance liquid chromatography (HPLC)-ECD, immunohistochemistry and Elisa. 1-methyl-4-phenylpyridinium (MPP+) concentration was tested by HPLC. Liver toxicity was determined by biochemical assay and histochemistry.
  
  
  RESULTS
  We found that the productions and/or expressions of several pro-inflammatory M1 factors such as nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 were highly suppressed by Tanshinone I in LPS-induced microglia. Interestingly, it did not affect the enhancement of expression of some anti-inflammatory M2 microglia markers, including IL-10, IL-1 receptor antagonist (IL-1Ra) and Cox-2. But it could significantly inhibit LPS-induced granulocyte colony-stimulating factor (G-CSF) expression. Tanshinone I could also inhibit LPS-induced NF-κB activation in microglia. Furthermore, it improved motor functions, normalized striatal neurotransmitters, and provided dopaminergic neuronal protection in MPTP-intoxicated mice. In vivo results also indicated that Tanshinone I could modulate MPTP-induced microglial activation, attenuated the increase of TNF-α, reserved the increase of IL-10 concentrain of MPTP-intoxicated mice. Tanshinone I does not alter MPTP toxic metabolite (MPP+) concentration. Oral administration of Tanshinone I at 10mg/kg daily for 2 weeks did not show liver toxicity.
  
  
  CONCLUSIONS
  Tanshinone I selectively suppressed pro-inflammatory M1 genes expression in activated microglia, interestingly, partially reserved anti-inflammatory M2 genes expression. It also could provide neuroprotection in a mouse model of Parkinson׳s disease. These data indicated that Tanshinone I could make the most of the beneficial side and minimize the detrimental side of activated microglia simultaneously, and provide neuroprotection by modulating the immune response of microglia.
authors: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Shaoxia
authors: S
authors: Wang
authors: Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Haoran
authors: H
authors: Jing
authors: Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Hongyun
authors: H
authors: Yang
authors: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Zhidong
authors: Z
authors: Liu
authors: Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Hong
authors: H
authors: Guo
authors: Tianjin Key Laboratory of Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Lijuan
authors: L
authors: Chai
authors: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China. Electronic address: huliminth@126.com.
authors: Limin
authors: L
authors: Hu
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D045784:Abietanes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001000:Ants; D002460:Cell Line; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects; D016328:NF-kappa B; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008517:Phytotherapy; D045442:Rotarod Performance Test
chemical_list: D045784:Abietanes; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008565:Membrane Proteins; D016328:NF-kappa B; D018696:Neuroprotective Agents; C021751:tanshinone; D009569:Nitric Oxide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (PubChem CID: 161406); 3,4-dihydroxyphenylacetic acid (PubChem CID: 547); Dopamine (PubChem CID: 65340); Homovanillic acid (PubChem CID: 1738); Inflammation; Microglia; Nitric oxide (PubChem CID: 145068); Parkinson; Tanshinone I; Tanshinone I (PubChem CID: 114917)