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Molecules 2011, 16(5), 4045-4058; doi:10.3390/molecules16054045

The Effects of Co-Treatment of 9-cis-Retinoic Acid and 15-Deoxy-Δ (12,14)-prostaglandin J2 on Microglial Activation

1
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan
2
Department of Pathology, University of Washington, Harborview Medical Center, Seattle, WA 98223, USA
3
Division of Mental Health and Addiction Medicine, the Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan
*
Author to whom correspondence should be addressed.
Received: 28 February 2011 / Revised: 26 April 2011 / Accepted: 16 May 2011 / Published: 17 May 2011
(This article belongs to the Special Issue Neuroactive Compounds)
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Abstract

Microglial activation plays an important role in the regulation of neuronal function and contributes to the development of neurodegeneration in Alzheimer’s disease (AD). Activation of nuclear peroxisome proliferator-activated receptor gamma (PPARγ) by an endogenous agonist, 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2), has been shown to be beneficial in many diseases with aberrant immune responses. Here, we report that co-treatment with 15d-PGJ2 and its synergistic partner, 9-cis-retinoic acid (RA), may modulate, but not abolish, microglial immune response activated by β-amyloid (Aβ) and interferon gamma (IFNγ). The co-treatment of RA and 15d-PGJ2 inhibited Aβ/IFNγ-activated immune response in primary microglia, as evidenced by suppressed expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2); and the effect was not affected by treatment with a PPARγ antagonist, GW9662. Data suggest that PPARγ activation may not contribute to the anti-inflammatory properties of the co-treatment. The co-treatment promoted microglial Aβ clearance in cultures; and the effect can be prevented by blocking PPARγ activation using GW9662. The effects of the co-treatment on Aβ clearance may be PPARγ-dependent. Intriguingly, secretion of microglial pro-nerve growth factor (pro-NGF) was inhibited by Aβ/IFNg treatment in a dose-dependent manner, suggesting that secretion of microglial pro-NGF may not contribute to the Ab/IFNg-activated microglial immune response. Taken together, the co-treatment may be beneficial for AD therapy; however, our data suggest that multiple mechanisms may underlie the beneficial effects of the co-treatment and are not limited to PPARγ activation only.
Keywords: Alzheimer’s disease; Aβ; microglia; PPARγ; neuroinflammation; pro-NGF Alzheimer’s disease; ; microglia; PPARγ; neuroinflammation; pro-NGF
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Hsu, P.-C.; Tsay, H.-J.; Montine, T.J.; Shie, F.-S. The Effects of Co-Treatment of 9-cis-Retinoic Acid and 15-Deoxy-Δ (12,14)-prostaglandin J2 on Microglial Activation. Molecules 2011, 16, 4045-4058.

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