The host anti-bacterial immune response that ensues during brain abscess development not only neutralizes pathogens but also contributes to the destruction of surrounding normal brain parenchyma. Limiting this pathological damage could result in long-term improvements for brain abscess patients. During the previous funding period, we found that the PPAR-? agonist ciglitazone accelerated abscess encapsulation/fibrosis, which coincided with a significant reduction in proinflammatory mediator expression as well as bacterial burdens. Since fibrosis typically ensues subsequent to the dampening of immune responses, it is possible that ciglitazone facilitates brain abscess wall formation by its ability to limit ongoing inflammation. Indeed, recent studies have demonstrated that PPAR-? agonists can transition classically activated (M1) macrophages into an alternatively activated (M2) phenotype as well as enhance the production of Th2 cytokines such as IL-4, IL-5, and IL-13, both of which are pro-fibrotic. However, the signal(s) responsible for regulating fibrosis during brain abscess development and the pathways influenced by ciglitazone to accelerate this process remain unknown. The overall hypothesis of this proposal is that the PPAR-? agonist ciglitazone accelerates brain abscess encapsulation through its ability to transition activated microglia/macrophages into a M2 alternative phenotype that, in turn, triggers a pro- fibrotic (Th2) cytokine profile to accelerate fibrosis. We will also utilize magnetic resonance imaging (MRI) modalities to monitor the effects of ciglitazone on brain abscess size, perfusion, and edema formation as well as density and organization of the abscess wall throughout disease development. These measures will provide a serial non-invasive assessment of brain abscess formation and how ciglitazone modulates these processes. MRI-based methods will include diffusion tensor imaging (DTI) for wall density and edema formation as well as high-resolution T1 and T2 MRI maps for clearly delineating the abscess wall from surrounding tissue. Perfusion maps will be used to monitor regional changes in blood flow along the brain abscess wall using arterial spin labeled (ASL) perfusion MRI. The power of these approaches is that MRI enables a longitudinal assessment of wall formation and perfusion throughout the course of brain abscess development in an individual animal. To address these objectives, the following specific aims will be investigated: 1) to investigate the mechanism(s) responsible for the PPAR-? agonist ciglitazone to accelerate brain abscess wall formation and fibrosis; and 2) to define the events influencing regulated fibrosis along the developing brain abscess wall. By understanding the mechanisms responsible for its ability to accelerate abscess encapsulation, ciglitazone may prove to be an effective adjunct therapy, in concert with conventional antibiotics, for the rapid containment of brain abscesses. Conceivably, this approach could lead to significant improvements in clinical outcomes and quality of life for patients recovering from brain abscesses.

Public Health Relevance

Brain abscesses represent a serious infection, especially due the recent emergence of antibiotic-resistant strains of bacteria, and can cause long-term deficits including seizures and cognitive loss. In this proposal, we will study a synthetic compound that causes brain abscesses to become walled off more rapidly, which may help to protect surrounding brain tissue from damage. This compound may prove beneficial, in combination with conventional antibiotics, for the treatment of brain abscess patients by facilitating rapid abscess containment, effectively limiting bacterial spread throughout the infected hemisphere.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040730-15
Application #
8514083
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2001-01-05
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
15
Fiscal Year
2013
Total Cost
$276,485
Indirect Cost
$90,300
Name
University of Nebraska Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Xiong, Juan; Burkovetskaya, Maria; Karpuk, Nikolay et al. (2012) IL-1RI (interleukin-1 receptor type I) signalling is essential for host defence and hemichannel activity during acute central nervous system bacterial infection. ASN Neuro 4:
Hanke, Mark L; Kielian, Tammy (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond) 121:367-87

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