title: Lithospermic acid attenuates 1-methyl-4-phenylpyridine-induced neurotoxicity by blocking neuronal apoptotic and neuroinflammatory pathways.
abstract: BACKGROUND
  Parkinson's disease is the second most common neurodegenerative disorders after Alzheimer's disease. The main cause of the disease is the massive degeneration of dopaminergic neurons in the substantia nigra. Neuronal apoptosis and neuroinflammation are thought to be the key contributors to the neuronal degeneration.
  
  
  RESULTS
  Both CATH.a cells and ICR mice were treated with 1-methyl-4-phenylpyridin (MPP(+)) to induce neurotoxicity in vitro and in vivo. Western blotting and immunohistochemistry were also used to analyse neurotoxicity, neuroinflammation and aberrant neurogenesis in vivo. The experiment in CATH.a cells showed that the treatment of MPP(+) impaired intake of cell membrane and activated caspase system, suggesting that the neurotoxic mechanisms of MPP(+) might include both necrosis and apoptosis. Pretreatment of lithospermic acid might prevent these toxicities. Lithospermic acid possesses specific inhibitory effect on caspase 3. In mitochondria, MPP(+) caused mitochondrial depolarization and induced endoplasmic reticulum stress via increasing expression of chaperone protein, GRP-78. All the effects mentioned above were reduced by lithospermic acid. In animal model, the immunohistochemistry of mice brain sections revealed that MPP(+) decreased the amount of dopaminergic neurons, enhanced microglia activation, promoted astrogliosis in both substantia nigra and hippocampus, and MPP(+) provoked the aberrant neurogenesis in hippocampus. Lithospermic acid significantly attenuates all of these effects induced by MPP(+).
  
  
  CONCLUSIONS
  Lithospermic acid is a potential candidate drug for the novel therapeutic intervention on Parkinson's disease.
authors.affiliation: National Research Institute of Chinese Medicine, 11221, Taipei, Taiwan, Republic of China. yllin@nricm.edu.tw.
authors.forename: Yun-Lian
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Institute of Neuroscience, Brain Research Center, National Yang-Ming University, 11221, Taipei, Taiwan, Republic of China. hjtsay@ym.edu.tw.
authors.forename: Huey-Jen
authors.initials: HJ
authors.lastname: Tsay
authors.affiliation: Institute of Biopharmaceutical Science, National Yang-Ming University, 11221, Taipei, Taiwan, Republic of China. sonic_9001@hotmail.com.
authors.forename: Tzu-Hsuan
authors.initials: TH
authors.lastname: Lai
authors.affiliation: Institute of Biopharmaceutical Science, National Yang-Ming University, 11221, Taipei, Taiwan, Republic of China. fly23242530@hotmail.com.
authors.forename: Tsai-Teng
authors.initials: TT
authors.lastname: Tzeng
authors.affiliation: National Research Institute of Chinese Medicine, 11221, Taipei, Taiwan, Republic of China. yshiao@nricm.edu.tw.|Institute of Biopharmaceutical Science, National Yang-Ming University, 11221, Taipei, Taiwan, Republic of China. yshiao@nricm.edu.tw.|Ph.D Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, 110, Taipei, Taiwan, Republic of China. yshiao@nricm.edu.tw.
authors.forename: Young-Ji
authors.initials: YJ
authors.lastname: Shiao
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D002460:Cell Line; D053630:Depsides / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D001572:Benzofurans; D053630:Depsides; C046833:lithospermic acid; D015655:1-Methyl-4-phenylpyridinium