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Drug Insight: effects mediated by peroxisome proliferator-activated receptor-γ in CNS disorders

Nature Clinical Practice Neurology volume 3, pages 496–504 (2007)Cite this article

Abstract

The finding that activation of peroxisome proliferator-activated receptor-γ (PPARγ) suppresses inflammation in peripheral macrophages and in models of human autoimmune disease instigated the evaluation of this salutary action for the treatment of CNS disorders with an inflammatory component. The fact that NSAIDs delay the onset of and reduce the risk of developing Alzheimer's disease (AD), while also binding to and activating PPARγ, led to the hypothesis that one dimension of NSAID protection in AD is mediated by PPARγ. Several lines of evidence from experiments using AD-related transgenic cellular and animal models have supported this hypothesis. The capacity of PPARγ agonists to elicit anti-inflammatory, anti-amyloidogenic and insulin-sensitizing effects might account for their observed protective effects. Several clinical trials employing PPARγ agonists have yielded promising results, and further trials are in preparation. Positive outcomes following PPARγ administration have been obtained in animal models of other neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, both of which are associated with a considerable degree of neuroinflammation. Finally, activation of PPARγ has been found to be protective in several models of multiple sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARγ activation in patients with multiple sclerosis.

Key Points

  • The evaluation of peroxisome proliferator-activated receptor gamma (PPARγ)-mediated actions for CNS disorders was prompted by experimental findings that showed that PPARγ activation suppresses inflammation in peripheral macrophages and in models of human autoimmune disease

  • Synthetic PPARγ ligands have been approved by the FDA and are currently in clinical use as oral treatments for non-insulin-dependent type 2 diabetes

  • Early clinical trials indicate that patients with Alzheimer's disease might benefit from the anti-amyloidogenic, anti-inflammatory and insulin-sensitizing effects of PPARγ activation

  • Positive outcomes in animal models of amyotrophic lateral sclerosis and Parkinson's disease indicate that patients with these conditions might benefit from PPARγ-activating drugs

  • Consistent with data from animal models, observations in a single patient and from a phase I study indicate a clinical benefit of PPARγ agonists in patients with multiple sclerosis

  • Studies in rodent models of cerebral ischemia showed neuroprotection in response to synthetic PPARγ activators, and a large clinical trial recently reported that a synthetic PPARγ agonist reduces the combined risk of heart attack, stroke and death in high-risk patients with type 2 diabetes

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Acknowledgements

MT Heneka was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG, HE 3350/6-1). GE Landreth was supported by grants from the NIH (AG16740) and the Blanchett Hooker Rockefeller Foundation. This publication is part of the German Research Network on Dementia and was funded by the German Federal Ministry for Education and Research (grant 01 G1 0420).

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Authors and Affiliations

  1. MT Heneka is a Professor of Molecular Neurology and a Senior Clinical Fellow in the Department of Neurology, University of Münster, Germany.,

    Michael T Heneka

  2. GE Landreth is a Professor of Neurosciences at Case Western Reserve University School of Medicine, Cleveland, OH, USA.,

    Gary E Landreth

  3. M Hüll is Professor of Geriatric Psychiatry and Head of the Centre of Geriatrics and Gerontology and the Section of Gerontopsychiatry and Neuropsychology, University of Freiburg, Germany.,

    Michael Hüll

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Correspondence to Michael T Heneka.

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Heneka, M., Landreth, G. & Hüll, M. Drug Insight: effects mediated by peroxisome proliferator-activated receptor-γ in CNS disorders. Nat Rev Neurol 3, 496–504 (2007). https://doi.org/10.1038/ncpneuro0586

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