A natural compound macelignan protects midbrain dopaminergic neurons from inflammatory degeneration via microglial arginase-1 expression.
Inflammatory events involving activated microglia have been recognized to play an important role in pathogenesis of various neurodegenerative disorders including Parkinson disease. Compounds regulating activation profiles of microglia may provide therapeutic benefits for Parkinson disease characterized by degeneration of midbrain dopaminergic neurons. Here we examined the effect of macelignan, a compound derived from nutmeg, on inflammatory degeneration of midbrain dopaminergic neurons. Treatment of midbrain slice cultures with interferon (IFN)-γ and lipopolysaccharide (LPS) caused a substantial decrease in viable dopaminergic neurons and an increase in nitric oxide (NO) production indicated by extracellular nitrite accumulation. Application of macelignan (10 μM) concomitantly with LPS prevented the loss of dopaminergic neurons. Besides nitrite accumulation, up-regulation of inducible NO synthase protein expression in response to IFN-γ/LPS was confirmed by Western blotting, and immunohistochemical examination revealed expression of inducible NO synthase in a subpopulation of Iba-1-poitive microglia. However, macelignan did not affect any of these NO-related parameters. On the other hand, macelignan promoted expression of arginase-1 in midbrain slice cultures irrespective of the presence or the absence of IFN-γ/LPS treatment. Arginase-1 expression was mainly localized in a subpopulation of Iba-1-positive cells. Importantly, the neuroprotective effect of macelignan was antagonized by N(ω)-hydroxy-nor-L-arginine, a specific arginase inhibitor. The neuroprotective effect of macelignan was also prevented by GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) antagonist. Overall, these results indicate that macelignan, a compound with PPARγ agonist activity, can provide neuroprotective effect on dopaminergic neurons in an arginase-dependent but NO-independent manner.
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Kana
K
Kiyofuji
Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan; Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Kumamoto, Japan.
Yuki
Y
Kurauchi
Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan; Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Kumamoto, Japan.
Akinori
A
Hisatsune
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Takahiro
T
Seki
Department of Food and Nutritional Sciences, Graduate School of Bioscience and Biotechnology, Chubu University, Kasugai, Japan.
Satoshi
S
Mishima
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: hkatsuki@gpo.kumamoto-u.ac.jp.
Hiroshi
H
Katsuki
D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000096:biosynthesis*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D008636:Mesencephalon / Q000187:drug effects / Q000201:enzymology*; D017628:Microglia / Q000187:drug effects / Q000201:enzymology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar
D017705:Lignans; D018696:Neuroprotective Agents; C502026:macelignan; D001119:Arginase; C542908:arginase I, rat
Alternative activation; Arginase; Microglia; Nitric oxide; Nitric oxide (PubChem:145068); Parkinson disease; Peroxisome proliferator-activated receptor