title: Baicalein attenuates α-synuclein aggregation, inflammasome activation and autophagy in the MPP+-treated nigrostriatal dopaminergic system in vivo.
abstract: BACKGROUND
  Neuroinflammation, oxidative stress, and protein aggregation form a vicious cycle in the pathophysiology of Parkinson's disease (PD); activated microglia is the main location of neuroinflammation. A Chinese medicine book, "Shanghan Lun", known as the "Treatises on Cold damage Diseases" has suggested that Scutellaria baicalensis Georgi is effective in treating CNS diseases. The anti-inflammatory mechanisms of baicalein, a phenolic flavonoid in the dried root of Scutellaria baicalensis Georgi, remain to be explored.
  
  
  OBJECTIVE
  The neuroprotective mechanisms of baicalein involving α-synuclein aggregation, inflammasome activation, and programmed cell death were investigated in the nigrostriatal dopaminergic system of rat brain in vivo.
  
  
  METHODS
  Intranigral infusion of 1-methyl-4-phenylpyridinium (MPP+, a Parkinsonian neurotoxin) was performed on anesthetized Sprague-Dawley rats. Baicalein was daily administered via intraperitoneal injection. Striatal dopamine levels were measured using high performance liquid chromatography coupled with electrochemical detection. Cellular signalings were measured by Western blot assay, immunofluorescent staining assay and enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Systemic administration of baicalein attenuated MPP+-induced reductions in striatal dopamine content and tyrosine hydroxylase (a biomarker of dopaminergic neurons) in the infused substantia nigra (SN). Furthermore, MPP+-induced elevations in α-synuclein aggregates (a pathological hallmark of PD), ED-1 (a biomarker of activated microglia), activated caspase-1 (a proinflammatory caspase), IL-1β and cathepsin B (a cysteine lysosomal protease) in the infused SN were attenuated in the baicalein-treated rats. Moreover, intense immunoreactivities of caspase 1 and cathepsin B were co-localized with that of ED-1 in the MPP+-infused SN. At the same time, baicalein inhibited MPP+-induced increases in active caspases 9 and 12 (biomarkers of apoptosis) as well as LC3-II levels (a biomarker of autophagy) in the rat nigrostriatal dopaminergic system.
  
  
  CONCLUSIONS
  Our in vivo study showed that baicalein possesses anti-inflammatory activities by inhibiting α-synuclein aggregation, inflammasome activation and cathepsin B production in the MPP+-infused SN. Moreover, baicalein is of therapeutic significance because it inhibits MPP+-induced apoptosis and autophagy in the nigrostriatal dopaminergic system of rat brain.
authors.affiliation: Department of Physiology, National Yang-Ming University, Taipei, Taiwan. Electronic address: q925134@hotmail.com.
authors.forename: Kai-Chih
authors.initials: KC
authors.lastname: Hung
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: hjhuang2@vghtpe.gov.tw.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Huang
authors.affiliation: Department of Physiology, National Yang-Ming University, Taipei, Taiwan. Electronic address: Claire-ting@hotmail.com.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Pharmacy, Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Electronic address: myalin@ym.edu.tw.
authors.forename: Anya Maan-Yuh
authors.initials: AM
authors.lastname: Lin
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D001343:Autophagy; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology*; D058847:Inflammasomes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D044950:Flavanones; D058847:Inflammasomes; D051844:alpha-Synuclein; C006680:baicalein; D015655:1-Methyl-4-phenylpyridinium
keywords: Autophagy; Baicalein; Caspase 1; Inflammasome activation; α-Synuclein aggregation