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

• Published in: British journal of pharmacology Vol. 165; no. 7; pp. 2213 - 2227
• Main Authors: Son, Hyo Jin, Lee, Ji Ae, Shin, Nari, Choi, Ji Hyun, Seo, Jai Woong, Chi, Dae Yoon, Lee, Cheol Soon, Kim, Eun‐Mee, Choe, Han, Hwang, Onyou
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2012; Nature Publishing Group
• Subjects: Animals; Antiparkinson Agents - metabolism; Antiparkinson Agents - pharmacology; Apoptosis; Base Sequence; Biological and medical sciences; Brain - metabolism; Cell Line; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; dopaminergic neuron; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - pathology; Dopaminergic Neurons - physiology; Matrix Metalloproteinase 3 - genetics; Matrix Metalloproteinase Inhibitors; Medical sciences; Mice; microglia; Microsomes, Liver - metabolism; MMP‐3; MPTP; MPTP Poisoning - complications; Nerve Degeneration - chemically induced; Nerve Degeneration - drug therapy; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Parkinson's disease; Parkinsonian Disorders - chemically induced; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - pathology; Parkinsonian Disorders - physiopathology; pharmacokinetics; Pharmacology. Drug treatments; Protease Inhibitors - metabolism; Protease Inhibitors - pharmacology; Research Papers; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Substantia Nigra - drug effects; Substantia Nigra - pathology; Substantia Nigra - physiopathology; Tetrahydroisoquinolines - metabolism; Tetrahydroisoquinolines - pharmacology; Animal model; Parkinson's disease; Neuroglia; Parkinson disease; Metalloendopeptidases; Prevention; Degenerative disease; Nervous system diseases; Dopamine; Enzyme; Catecholamine; Cerebral disorder; Microglia; Peptidases; Toxin; Central nervous system disease; Neurotoxin; MMP-3; Neurotransmitter; Hydrolases; Dopaminergic neuron; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP; Pharmacokinetics; Extrapyramidal syndrome
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01692.x

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.