title: 2-Acetyl-7-hydroxy-6-methoxy-1-methyl-1,2,3,4,-tetrahydroisoquinoline exhibits anti-inflammatory properties and protects the nigral dopaminergic neurons.
abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopamine(DA)ergic neurons. Neuroinflammation caused by microglial activation is believed to be involved in the pathogenesis of neurodegenerative diseases including PD. In the present study, we tested the effects of a novel compound 2-acetyl-7-hydroxy-6-methoxy-1-methyl-1,2,3,4,-tetarhydroisoquinoline (AMTIQ) on neuroinflammatory response and DAergic neurodegeneration. In lipopolysaccharide-activated BV-2 microglial cells, AMTIQ lowered nitric oxide and tetrahydrobiopterin levels and downregulated gene expression of inducible nitric oxide synthase and GTP cyclohydrolase I. AMTIQ also repressed gene expression of the proinflammatory cytokines IL-1β and TNF-α, and attenuated nuclear translocation of NF-κB. AMTIQ was stable against liver microsomal enzymes from human and mouse and did not interfere with activities of the cytochrome p450 enzymes 1A2, 2D6, 2C9, 2C19 and 3A4. Pharmacokinetic studies revealed the brain to plasma ratio of AMTIQ to be 45%, suggesting it can penetrate the blood brain barrier. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse PD model, AMTIQ led to decreased microglial activation, increased survival of DAergic neurons and their fibers, and improved behavioral scores on rotarod and vertical grid tests. Taken together, these results suggest that AMTIQ might serve as a candidate preventive-therapeutic agent for neurodegenerative diseases such as PD.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Son
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Se Hee
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Ji Ae
authors.initials: JA
authors.lastname: Lee
authors.affiliation: R&D Institute of Nanomol, Incheon, South Korea.
authors.forename: Cheol Soon
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Inha University, Incheon, South Korea.
authors.forename: Jai Woong
authors.initials: JW
authors.lastname: Seo
authors.affiliation: Department of Chemistry, Inha University, Incheon, South Korea; Department of Chemistry, Sogang University, Seoul, South Korea. Electronic address: dychi@sogang.ac.kr.
authors.forename: Dae Yoon
authors.initials: DY
authors.lastname: Chi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea. Electronic address: oyhwang@amc.seoul.kr.
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D059290:Dopaminergic Neurons / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects*
chemical_list: C000611679:2-acetyl-7-hydroxy-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline; D000893:Anti-Inflammatory Agents; D000978:Antiparkinson Agents; D016207:Cytokines; D007546:Isoquinolines; D018696:Neuroprotective Agents; D009569:Nitric Oxide
keywords: Microglia; Motor deficits; Neuroinflammation; Parkinson’s disease; Substantia nigra