2-Acetyl-7-hydroxy-6-methoxy-1-methyl-1,2,3,4,-tetrahydroisoquinoline exhibits anti-inflammatory properties and protects the nigral dopaminergic neurons

• Published in: European journal of pharmacology Vol. 771; pp. 152 - 161
• Main Authors: Son, Hyo Jin, Han, Se Hee, Lee, Ji Ae, Lee, Cheol Soon, Seo, Jai Woong, Chi, Dae Yoon, Hwang, Onyou
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.01.2016
• Subjects: Animals; Anti-Inflammatory Agents - pharmacokinetics; Anti-Inflammatory Agents - pharmacology; Antiparkinson Agents - pharmacokinetics; Antiparkinson Agents - pharmacology; Blood-Brain Barrier - metabolism; Brain - metabolism; Cell Line; Cytokines - biosynthesis; Cytokines - genetics; Dopaminergic Neurons - drug effects; Humans; In Vitro Techniques; Isoquinolines - pharmacokinetics; Isoquinolines - pharmacology; Macrophage Activation - drug effects; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Microglia; Microglia - drug effects; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Motor deficits; Neuroinflammation; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Nitric Oxide - metabolism; Parkinson’s disease; Substantia nigra; Substantia Nigra - cytology; Substantia Nigra - drug effects; DAergic; PBS; NO; RT; Substantia nigra; GTPCH; AMTIQ; Neuroinflammation; Motor deficits; LPS; BH4; Microglia; NF-κB; PD; TH; TNF-α; iNOS; CYP; MPTP; SN; PCR; Parkinson’s disease; ELISA
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.12.009

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.