Abstract
Agents suppressing microglial activation are attracting attention as candidate drugs for neuroprotection in Parkinson s disease (PD): While different mechanisms including environmental toxins and genetic factors initiate neuronal damage in the substantia nigra and striatum in PD, there is unequivocal evidence that activation of neuroinflammatory cells aggravates this neurodegenerative process. It was shown that following an acute exposure to the neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other toxins the degenerative process continues for years in absence of the toxin. Reactive microglia has been observed in the substantia nigra of patients with PD, indicating that this inflammatory process might aggravate neurodegeneration. By releasing various kinds of noxious factors such as cytokines or proinflammatory molecules microglia may damage CNS cells. The stimuli triggering microgliosis in Parkinsonian syndromes are unknown so far: However, analysis of neuronal loss in PD patients shows that it is not uniform but that neurons containing neuromelanin (NM) are predominantly involved. We hypothesized that extraneuronal melanin might trigger microgliosis, microglial chemotaxis and microglial activation in PD with subsequent release of neurotoxic mediators. The addition of human NM to microglial cell cultures induced positive chemotactic effects, activated the proinflammatory transcription factor nuclear factor kappa B (NF-κB) via phosphorylation and degradation of the inhibitor protein κB (IκB), and led to an upregulation of TNF-α, IL-6 and NO. These findings demonstrate a crucial role of NM in the pathogenesis of Parkinsons disease by augmentation of microglial activation, leading to a vicious cycle of neuronal death, exposure of additional neuromelanin and chronification of inflammation. Antiinflammatory drugs may be one of the new approaches in the treatment of PD.
Keywords: Microglia, Parkinson's disease, neuroinflammation
Current Pharmaceutical Design
Title: Inflammation in Parkinsons Diseases and Other Neurodegenerative Diseases: Cause and Therapeutic Implications
Volume: 13 Issue: 18
Author(s): H. Wilms, L. Zecca, P. Rosenstiel, J. Sievers, G. Deuschl and R. Lucius
Affiliation:
Keywords: Microglia, Parkinson's disease, neuroinflammation
Abstract: Agents suppressing microglial activation are attracting attention as candidate drugs for neuroprotection in Parkinson s disease (PD): While different mechanisms including environmental toxins and genetic factors initiate neuronal damage in the substantia nigra and striatum in PD, there is unequivocal evidence that activation of neuroinflammatory cells aggravates this neurodegenerative process. It was shown that following an acute exposure to the neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other toxins the degenerative process continues for years in absence of the toxin. Reactive microglia has been observed in the substantia nigra of patients with PD, indicating that this inflammatory process might aggravate neurodegeneration. By releasing various kinds of noxious factors such as cytokines or proinflammatory molecules microglia may damage CNS cells. The stimuli triggering microgliosis in Parkinsonian syndromes are unknown so far: However, analysis of neuronal loss in PD patients shows that it is not uniform but that neurons containing neuromelanin (NM) are predominantly involved. We hypothesized that extraneuronal melanin might trigger microgliosis, microglial chemotaxis and microglial activation in PD with subsequent release of neurotoxic mediators. The addition of human NM to microglial cell cultures induced positive chemotactic effects, activated the proinflammatory transcription factor nuclear factor kappa B (NF-κB) via phosphorylation and degradation of the inhibitor protein κB (IκB), and led to an upregulation of TNF-α, IL-6 and NO. These findings demonstrate a crucial role of NM in the pathogenesis of Parkinsons disease by augmentation of microglial activation, leading to a vicious cycle of neuronal death, exposure of additional neuromelanin and chronification of inflammation. Antiinflammatory drugs may be one of the new approaches in the treatment of PD.
Export Options
About this article
Cite this article as:
H. Wilms , L. Zecca , P. Rosenstiel , J. Sievers , G. Deuschl and R. Lucius , Inflammation in Parkinsons Diseases and Other Neurodegenerative Diseases: Cause and Therapeutic Implications, Current Pharmaceutical Design 2007; 13 (18) . https://dx.doi.org/10.2174/138161207780858429
DOI https://dx.doi.org/10.2174/138161207780858429 |
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
?Revolutionizing Cancer Treatment: Nano-Therapeutics Targeting Tumor Microenvironment?
This thematic issue explores the forefront of cancer treatment, centering on the groundbreaking potential of nano-therapeutics meticulously designed to target the tumor microenvironment. At its core, the issue aims to unravel the latest advancements in nanotechnology, showcasing innovative materials, formulations, and delivery systems that hold promise for redefining cancer therapeutics. ...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
- 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
-
The Study of HLA Class II and Autoimmune Diabetes
Current Molecular Medicine The Role of Adipocytokines in Atherogenesis and Atheroprogression
Current Drug Targets Immunomodulation in Multiple Sclerosis by Phytotherapy
Current Immunology Reviews (Discontinued) Therapeutical Potential of CB<sub>2</sub> Receptors in Immune-Related Diseases
Current Molecular Pharmacology Targeting Interleukin-21 in Immune-Mediated Pathologies
Current Drug Targets Monocyte Dependent Regulation of Autoimmune Inflammation
Current Molecular Medicine Circumscribing the Conformational Peptide Epitope Landscape
Current Pharmaceutical Design Autoantibodies in Autoimmune Diseases
Current Pharmaceutical Design Heme Oxygenase-1 as a Target for the Design of Gene and Pharmaceutical Therapies for Autoimmune Diseases
Current Gene Therapy Role for Poly(ADP-ribose) Polymerase Activation in Diabetic Nephropathy, Neuropathy and Retinopathy
Current Vascular Pharmacology Age-Dependent Microglial Activation in Immature Brains After Hypoxia- Ischemia
CNS & Neurological Disorders - Drug Targets Therapeutic Perspectives of Inhibitors of Endocannabinoid Degradation
Current Drug Targets - CNS & Neurological Disorders Gene Therapy for Neuroprotection and Neurorestoration (Part I)
Current Gene Therapy Targeted Drug Delivery to Central Nervous System (CNS) for the Treatment of Neurodegenerative Disorders: Trends and Advances
Central Nervous System Agents in Medicinal Chemistry Pediatric Immune Dysfunction and Health Risks Following Early-Life Immune Insult
Current Pediatric Reviews The Blood-Central Nervous System Barriers Actively Control Immune Cell Entry into the Central Nervous System
Current Pharmaceutical Design Role of Estradiol and Progesterone in HIV Susceptibility and Disease Progression
Mini-Reviews in Medicinal Chemistry Therapeutic Targeting of Epigenetic Components in Amyotrophic Lateral Sclerosis (ALS)
Current Medicinal Chemistry The Role of miR-124 in Drosophila Alzheimer's Disease Model by Targeting Delta in Notch Signaling Pathway
Current Molecular Medicine Estrogen and Cytokines Production - The Possible Cause of Gender Differences in Neurological Diseases
Current Pharmaceutical Design