Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists
Open accessAbstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ2) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZD-induced neuroprotection in various animal models of CNS injury with an emphasis on stroke.
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The antidepressant properties of pioglitazone appeared to be largely independent of insulin-sensitizing action and possibly mediated by anti-inflammatory and antioxidant actions, including inhibition of the nuclear factor kappa B cascade and cytokine production, as well as quinolinic acid-induced neurotoxicity.
“Importantly, the authors of this study underscored that antidepressant properties appeared to be largely independent of insulin-sensitizing action and are possibly mediated by anti-inflammatory and antioxidant”
From Cognitive remission: a novel objective for the treatment of major depression? (2016) · cites this paper as [119]
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- Mrak R. E. & G. E. Landreth: PPAR-gamma, neuroinflammation and disease. J Neuroinflammation 1, 5 (2004)
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- Authors
- Kapadia, R.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Kapadia, Ramya
- Venue
- Frontiers in Bioscience
- Publisher
- IMR Press
- Published
- 2008
- Volume
- 13
- Issue
- 13
- Pages
- 1813
- ISSN
- 1093-4715 (ISSN-L)
- 1093-9946
- DOI
- 10.2741/2802
- PMC
- PMC2734868
- OpenAlex
- W2073874214
- Cited by
- 433
- References
- 129
- Citations by year
- 2026: 19 · 2025: 21 · 2024: 25 · 2023: 22 · 2022: 29 · 2021: 30 · 2020: 25 · 2019: 28 · 2018: 30 · 2017: 21 · 2016: 29 · 2015: 24 · 2014: 21 · 2013: 18 · 2012: 18
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Frontiers in bioscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5r01ns044173-02, 5r01ns049448-04, 0350164 N, RO1 NS049448, RO1 NS044173)
- National Institute of Neurological Disorders and Stroke (R01-NS044173, R01-NS049448)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- PPARγ agonists, thiazolidinediones, neuroprotection, anti-inflammatory mechanism, stroke, spinal cord injury, traumatic brain injury, focal cerebral ischemia, microglial activation, inflammatory cytokines, chemokines, oxidative stress, rosiglitazone, pioglitazone, 15-deoxy-delta12-prostaglandin J2, central nervous system injury
- MeSH terms
- Animals, Anti-Inflammatory Agents, Brain Ischemia, Humans, Inflammation, Ischemia, Ligands, Spinal Cord Injuries, Reactive Oxygen Species, Oxidative Stress, Neuroprotective Agents, Stroke, PPAR delta, PPAR gamma, PPAR-beta
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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