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-α, IL-1β 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-α and IL-1β pathways as well as MAPK and NF-κB 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 UCBinduced 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.
Keywords: Cell death mechanisms, glutamate, glycoursodeoxycholic acid, inflammatory signaling pathways, interleukin-10, minocycline, nerve cells, unconjugated bilirubin
Current Pharmaceutical Design
Title: Contribution of Inflammatory Processes to Nerve Cell Toxicity by Bilirubin and Efficacy of Potential Therapeutic Agents
Volume: 15 Issue: 25
Author(s): Adelaide Fernandes and Dora Brites
Affiliation:
Keywords: Cell death mechanisms, glutamate, glycoursodeoxycholic acid, inflammatory signaling pathways, interleukin-10, minocycline, nerve cells, unconjugated bilirubin
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-α, IL-1β 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-α and IL-1β pathways as well as MAPK and NF-κB 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 UCBinduced 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.
Export Options
About this article
Cite this article as:
Fernandes Adelaide and Brites Dora, Contribution of Inflammatory Processes to Nerve Cell Toxicity by Bilirubin and Efficacy of Potential Therapeutic Agents, Current Pharmaceutical Design 2009; 15 (25) . https://dx.doi.org/10.2174/138161209789058165
DOI https://dx.doi.org/10.2174/138161209789058165 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Humanized Cobra Venom Factor: Experimental Therapeutics for Targeted Complement Activation and Complement Depletion
Current Pharmaceutical Design Roles of EGFR, PI3K, AKT, and mTOR in Heavy Metal-Induced Cancer
Current Cancer Drug Targets Topotecan and Irinotecan in the Treatment of Pediatric Solid Tumors
Current Pediatric Reviews Ignored Avenues in Alpha-Synuclein Associated Proteopathy
CNS & Neurological Disorders - Drug Targets Editorial [Hot Topic:Treatment of Neuroblastoma: From Cellular to Molecular Therapy (Executive Editor: Gian Paolo Tonini)]
Current Pharmaceutical Design Artificial Intelligence, Big Data and Machine Learning Approaches in Precision Medicine & Drug Discovery
Current Drug Targets Semaphorins and their Receptors in Stem and Cancer Cells
Current Medicinal Chemistry Anti-Amyloidogenic and Anti-Apoptotic Role of Melatonin in Alzheimer Disease
Current Neuropharmacology Estrogen Receptor-Positive and Estrogen Receptor-Negative Human Breast Cancer Cells: Regulation of Expression of Cancer-Related Genes by Estradiol and Tamoxifen
Current Signal Transduction Therapy Rapid Non-genomic Vasodilator Actions of Oestrogens and Sex Steroids
Current Medicinal Chemistry Synthesis of the Alzheimer Drug Posiphen into its Primary Metabolic Products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their Inhibition of Amyloid Precursor Protein, α -Synuclein Synthesis, Interleukin-1β Release, and Cholinergic Action.
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Discovery of Selective Probes and Antagonists for G Protein-Coupled Receptors FPR/FPRL1 and GPR30
Current Topics in Medicinal Chemistry Prospects for Preventative Vaccines Against Prion Diseases
Protein & Peptide Letters The Role of Tregs in Cancer: Foxp3 as a Putative Target for Therapy
Current Signal Transduction Therapy Peptides or Small Molecules? Different Approaches to Develop More Effective CDK Inhibitors
Current Medicinal Chemistry HIV-1 gp120 and Drugs of Abuse: Interactions in the Central Nervous System
Current HIV Research Recent Advances in Biological Tissue Imaging with Time-of-Flight Secondary Ion Mass Spectrometry: Polyatomic Ion Sources, Sample Preparation, and Applications
Current Pharmaceutical Design Anticancer Mechanisms of Berberine: A Good Choice for Glioblastoma Multiforme Therapy
Current Medicinal Chemistry Neuronal Acetylcholine Nicotinic Receptors as New Targets for Lung Cancer Treatment
Current Pharmaceutical Design Sirtuins: Possible Clinical Implications in Cardio and Cerebrovascular Diseases
Current Drug Targets