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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
A natural compound macelignan protects midbrain dopaminergic neurons from inflammatory degeneration via microglial
Kana Kiyofuji1, Yuki Kurauchi2, Akinori Hisatsune2
1Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Abstract:
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.
Insights
Macelignan, a compound from nutmeg, protects dopaminergic neurons in Parkinson disease models by increasing arginase-1, not nitric oxide. This neuroprotective effect is mediated through peroxisome proliferator-activated receptor gamma (PPARγ) activation.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Microglia activation is key in neurodegenerative diseases like Parkinson's.
- Targeting microglial inflammatory pathways offers therapeutic potential for Parkinson disease.
Purpose of the Study:
- To investigate the neuroprotective effects of macelignan on midbrain dopaminergic neurons against inflammatory damage.
- To elucidate the mechanisms underlying macelignan's action, focusing on nitric oxide and arginase pathways.
Main Methods:
- Primary midbrain slice cultures were treated with interferon-gamma (IFN-γ) and lipopolysaccharide (LPS) to induce inflammation.
- Macelignan's effects on dopaminergic neuron viability, nitric oxide (NO) production, inducible NO synthase (iNOS), and arginase-1 expression were assessed.
- Western blotting, immunohistochemistry, and pharmacological inhibitors (arginase inhibitor, PPARγ antagonist) were employed.
Main Results:
- IFN-γ/LPS treatment reduced dopaminergic neuron survival and increased NO production.
- Macelignan (10 μM) prevented dopaminergic neuron loss without affecting NO-related parameters.
- Macelignan upregulated arginase-1 expression in microglia and its neuroprotective effect was blocked by an arginase inhibitor and a PPARγ antagonist.
Conclusions:
- Macelignan exerts neuroprotection in a Parkinson disease model via an arginase-dependent, NO-independent mechanism.
- The compound acts as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, highlighting its therapeutic potential.
