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The Synthetic Peroxisome Proliferator-Activated Receptor- Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses¹

Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205

Brain abscesses result from a pyogenic parenchymal infection commonly initiated by Gram-positive bacteria such as Staphylococcus aureus. Although the host immune response elicited following infection is essential for effective bacterial containment, this response also contributes to the significant loss of brain parenchyma by necrosis that may be reduced by modulating the inflammatory response. Ciglitazone, a PPAR- agonist with anti-inflammatory properties, was evaluated for its ability to influence the course of brain abscess development when treatment was initiated 3 days following infection. Interestingly, abscess-associated bacterial burdens were significantly lower following ciglitazone administration, which could be explained, in part, by the finding that ciglitazone enhanced S. aureus phagocytosis by microglia. In addition, ciglitazone attenuated the expression of select inflammatory mediators during brain abscess development including inducible NO synthase, TNF-, IL-1β, CXCL2, and CCL3. Unexpectedly, ciglitazone also accelerated brain abscess encapsulation, which was typified by the heightened expression of fibronectin and -smooth muscle actin-positive myofibroblasts. Collectively, through its ability to attenuate excessive inflammation and accelerate abscess encapsulation, ciglitazone may effectively sequester brain abscesses and limit bacterial dissemination.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by 2RO1 NS40730 from the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) (to T.K.) and P30 NS047546 from the NINDS-supported Core Facility at the University of Arkansas for Medical Sciences. Support for the Digital and Confocal Microscopy Laboratory at the University of Arkansas for Medical Sciences is provided by Grant P20 RR6460 from NIH/IDeA Network of Biomedical Research Excellence and Grant S10 RR19395 from NIH/National Center for Research Resources.

² Address correspondence and reprint requests to Dr. Tammy Kielian, Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 846, Little Rock, AR 72205. E-mail address: KielianTammyL{at}uams.edu

³ Abbreviations used in this paper: PPAR-, peroxisome proliferator-activated receptor-; iNOS, inducible NO synthase; PGN, peptidoglycan; 15d-PGJ₂, 15-deoxy-^12,14-PGJ₂; EAE, experimental autoimmune encephalomyelitis.

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