Referenced in: none

Automatically associated channels: Kv11.1 , Slo1

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

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

Journal, date & volume: Br. J. Pharmacol., 2012 Apr , 165, 2213-27

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21951056

Abstract
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.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.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.These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson's disease.