title: A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson's disease induced by MPTP.
abstract: OBJECTIVE
  In Parkinson's disease, the dopaminergic neurones in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is not completely understood, neuronal apoptosis and neuroinflammation are thought to be key contributors. We have recently established that MMP-3 plays crucial roles in dopaminergic cell death and microglial activation.
  
  
  METHODS
  We tested the effects of 7-hydroxy-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) on expression of MMP-3 and inflammatory molecules and dopaminergic cell death in vitro and in an animal model of Parkinson's disease, and Parkinson's disease-related motor deficits. The pharmacokinetic profile of PTIQ was also evaluated.
  
  
  RESULTS
  PTIQ effectively suppressed the production of MMP-3 induced in response to cellular stress in the dopaminergic CATH.a cell line and prevented the resulting cell death. In BV-2 microglial cells activated with lipopolysaccharide, PTIQ down-regulated expression of MMP-3 along with IL-1β, TNF-α and cyclooxygenase-2 and blocked nuclear translocation of NF-κB. In the mouse model of Parkinson's disease ,induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), PTIQ attenuated the associated motor deficits, prevented neurodegeneration and suppressed microglial activation in the substantia nigra. Pharmacokinetic analysis showed it was relatively stable against liver microsomal enzymes, did not inhibit the cytochrome p450 isozymes or the hERG ion channel, exhibited no cytotoxicity on liver cells or lethality when administered at 1000 mg kg(-1) and entered the brain rather rapidly yielding a 28% brain:plasma ratio after i.p. injection.
  
  
  CONCLUSIONS
  These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson's disease.
authors.affiliation: Department of Biochemistry, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Son
authors.forename: Ji Ae
authors.initials: JA
authors.lastname: Lee
authors.forename: Nari
authors.initials: N
authors.lastname: Shin
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Jai Woong
authors.initials: JW
authors.lastname: Seo
authors.forename: Dae Yoon
authors.initials: DY
authors.lastname: Chi
authors.forename: Cheol Soon
authors.initials: CS
authors.lastname: Lee
authors.forename: Eun-Mee
authors.initials: EM
authors.lastname: Kim
authors.forename: Han
authors.initials: H
authors.lastname: Choe
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D020267:MPTP Poisoning / Q000150:complications; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D044005:Tetrahydroisoquinolines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000978:Antiparkinson Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; C046152:1-(2-methyl-3-hydroxy-5-hydroxymethyl-4-pyridyl)-6,7-dihydroxy-1,2-3,4-tetrahydroisoquinoline; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse