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Contribution of inflammatory processes to nerve cell toxicity by bilirubin and efficacy of potential therapeutic agents.
- Source :
-
Current pharmaceutical design [Curr Pharm Des] 2009; Vol. 15 (25), pp. 2915-26. - Publication Year :
- 2009
-
Abstract
- Hyperbilirubinemia is a common condition in neonatal life, where elevated levels of unconjugated bilirubin (UCB) may lead to adverse neurologic outcomes, namely in the presence of inflammatory features. In this review, we summarize recent concepts on UCB damage to brain cells and associated neuroinflammation research. Exposure of astrocytes and microglia to UCB initiates an inflammatory response with the release of proinflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6, accumulation of extracellular glutamate and a time-dependent cell death. Moreover, undifferentiated cells revealed to be particularly susceptible to UCB-induced immunostimulation pointing to a mechanism that may preside to the vulnerability evidenced by premature newborns. Evaluation of intracellular mechanisms of astrocyte and microglia to UCB revealed that TNF-alpha and IL-1beta pathways as well as MAPK and NF-kappaB signaling cascades are key mediators of both cytokine production and cell toxicity observed upon UCB challenge. Understanding these mechanisms is essential for the development of new strategies targeting UCB-induced neurotoxicity. Thus, a therapeutic approach for the prevention or amelioration of neurological deficits resulting from moderate to severe hyperbilirubinemia, may consist on the use of immunomodulators, such as IL-10 that showed ability to suppress the release of cytokines from astrocytes exposed to UCB, glycoursodeoxycholic acid (GUDCA) that abrogated both UCB-stimulated cytokine secretion and UCB-induced loss of cell survival, and minocycline that evidenced a unique role in preventing neurodegeneration in in vitro and in vivo models. Novel pharmacological strategies may reduce the incidence of UCB encephalopathy and prevent minor cerebral lesions that may result in mental illness.
- Subjects :
- Animals
Anti-Inflammatory Agents therapeutic use
Cell Death
Cell Differentiation
Central Nervous System Diseases metabolism
Central Nervous System Diseases pathology
Central Nervous System Diseases prevention & control
Cytokines metabolism
Glutamic Acid metabolism
Humans
Hyperbilirubinemia drug therapy
Hyperbilirubinemia metabolism
Hyperbilirubinemia pathology
Hyperbilirubinemia, Neonatal complications
Hyperbilirubinemia, Neonatal drug therapy
Hyperbilirubinemia, Neonatal pathology
Immunologic Factors therapeutic use
Infant, Newborn
Inflammation drug therapy
Inflammation metabolism
Inflammation pathology
Inflammation Mediators metabolism
Kernicterus etiology
Kernicterus metabolism
Neurons pathology
Neuroprotective Agents therapeutic use
Signal Transduction
Bilirubin metabolism
Central Nervous System Diseases etiology
Hyperbilirubinemia complications
Inflammation etiology
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4286
- Volume :
- 15
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Current pharmaceutical design
- Publication Type :
- Academic Journal
- Accession number :
- 19754368
- Full Text :
- https://doi.org/10.2174/138161209789058165