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The Effects of Co-Treatment of 9-cis-Retinoic Acid and 15-Deoxy-Δ (12,14)-prostaglandin J2 on Microglial Activation
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan
Department of Pathology, University of Washington, Harborview Medical Center, Seattle, WA 98223, USA
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; in revised form: 26 April 2011 / Accepted: 16 May 2011 / Published: 17 May 2011
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
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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.
Hsu P-C, Tsay H-J, Montine TJ, 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(5):4045-4058.
Hsu, Pei-Chien; Tsay, Huey-Jen; Montine, Thomas J.; Shie, Feng-Shiun. 2011. "The Effects of Co-Treatment of 9-cis-Retinoic Acid and 15-Deoxy-Δ (12,14)-prostaglandin J2 on Microglial Activation." Molecules 16, no. 5: 4045-4058.