Brain abscesses represent an important medical problem despite recent advances made in detection and therapy. Because of the emergence of multi-drug resistant strains and the ubiquitous nature of bacteria, these CNS infections are likely to persist. The size of a developing abscess normally extends well beyond the original site of infection leading to damage of surrounding normal brain parenchyma. This finding suggests that the CNS antibacterial response is not down regulated in an efficient manner, resulting in chronic inflammation and large abscess lesions. They propose that a balance exists between sufficient and over-compensatory responses to S. aureus in the CNS, which dictates the outcome of brain abscess development; therefore, therapies aimed at attenuating chronic CNS inflammation subsequent to effective bacterial neutralization may result in smaller abscesses and subsequent improvements in cognitive and neurological functions. The objective of the proposed work is to examine the influences of minocycline and PPAR-gamma agonists on the pathogenesis of brain abscess development. Recently, these compounds have been found to exhibit neuroprotective effects in several models of CNS disease; however, their roles in regulating CNS infectious disease has not yet been examined. To address this objective, the following Specific Aims will be addressed: (I) to evaluate the dose- and time-dependent effects of PPAR-gamma agonists and minocycline on S. aureus-induced brain abscess development; (II) to investigate the effects of PPAR-gamma agonists and minocycline on cell migration and neuronal cell death induced by S. aureus-stimulated microglia; and (III) to examine the mechanism(s) responsible for impaired neutrophil infiltration into brain abscesses of CXCR2 KO mice and the potential effects of PPAR-gamma agonists and minocycline in the CNS compartment. In addition to its anti-inflammatory properties, the bacteriostatic activity of minocycline may augment its effects on brain abscess development. The potential multifactorial effects of these compounds suggest that they may be more efficacious compared to traditional therapies developed to counteract a single pathway in CNS diseases. These experiments should provide meaningful insights into how minocycline and PPAR-gamma agonists influence brain abscess development and will reveal whether their ability to modulate non-infectious CNS conditions extends to infectious diseases.
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