A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson's disease induced by MPTP

Hyo Jin Son, Ji Ae Lee, Nari Shin, Ji Hyun Choi, Jai Seo, Dae Yoon Chi, Cheol Soon Lee, Eun Mee Kim, Han Choe, Onyou Hwang

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)2213-2227
Number of pages15
JournalBritish Journal of Pharmacology
Volume165
Issue number7
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

Keywords

  • dopaminergic neuron
  • microglia
  • MMP-3
  • MPTP
  • Parkinson's disease
  • pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology

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