Abstract
Aberrations in nitrergic neurotransmission, due to a decrease in neuronal nitric oxide (NO) synthase (nNOS) protein, play an important role in the pathogenesis of autonomic neuropathy in diabetes. Until recently the mechanism of the decrease in nNOS protein content in nitrergic nerves during diabetes was debated. Two different views were prevailing, one attributing the nNOS decrease to nitrergic nerve degeneration, the other to an alteration in nNOS expression. Our recent study in which we showed that nitrergic nerves undergo a degenerative process in two phases might bring a solution to this debate. Our model suggests that, in the early stages of diabetes, nNOS expression is decreased in the nitrergic axons while nNOS levels are unaffected in the cell bodies, most probably due to a defect in axonal transport. This decrease is reversible with insulin treatment. As the diabetes progresses, nNOS starts to accumulate in the cell bodies since it cannot be transported down to the axons. Increased nNOS protein and NO production coincide with accumulation of advanced glycation endproducts (AGEs) in the blood and tissues. Synergistic action of AGEs and endogenous NO leads to increased oxidative stress within the cell bodies, resulting in apoptosis. This degenerative phase of nitrergic neuropathy is not reversible with insulin treatment. This suggests a point of no return for autonomic nerves after which the degenerative changes become irreversible. Future therapeutic approaches could target the defective axonal transport and prevention of AGEs accumulation before this point of no return. In the later stages, reduction of AGEs, replenishment of lost nitrergic neurons and restoration of function are putative therapeutic targets.
Keywords: nitric oxide, nitrergic, autonomic, diabetes mellitus, erectile dysfunction, diabetic complications, advanced, glycation endproducts, axonal transport
Current Pharmaceutical Design
Title: Point of NO Return for Nitrergic Nerves in Diabetes: A New Insight into Diabetic Complications
Volume: 10 Issue: 29
Author(s): S. Cellek
Affiliation:
Keywords: nitric oxide, nitrergic, autonomic, diabetes mellitus, erectile dysfunction, diabetic complications, advanced, glycation endproducts, axonal transport
Abstract: Aberrations in nitrergic neurotransmission, due to a decrease in neuronal nitric oxide (NO) synthase (nNOS) protein, play an important role in the pathogenesis of autonomic neuropathy in diabetes. Until recently the mechanism of the decrease in nNOS protein content in nitrergic nerves during diabetes was debated. Two different views were prevailing, one attributing the nNOS decrease to nitrergic nerve degeneration, the other to an alteration in nNOS expression. Our recent study in which we showed that nitrergic nerves undergo a degenerative process in two phases might bring a solution to this debate. Our model suggests that, in the early stages of diabetes, nNOS expression is decreased in the nitrergic axons while nNOS levels are unaffected in the cell bodies, most probably due to a defect in axonal transport. This decrease is reversible with insulin treatment. As the diabetes progresses, nNOS starts to accumulate in the cell bodies since it cannot be transported down to the axons. Increased nNOS protein and NO production coincide with accumulation of advanced glycation endproducts (AGEs) in the blood and tissues. Synergistic action of AGEs and endogenous NO leads to increased oxidative stress within the cell bodies, resulting in apoptosis. This degenerative phase of nitrergic neuropathy is not reversible with insulin treatment. This suggests a point of no return for autonomic nerves after which the degenerative changes become irreversible. Future therapeutic approaches could target the defective axonal transport and prevention of AGEs accumulation before this point of no return. In the later stages, reduction of AGEs, replenishment of lost nitrergic neurons and restoration of function are putative therapeutic targets.
Export Options
About this article
Cite this article as:
Cellek S., Point of NO Return for Nitrergic Nerves in Diabetes: A New Insight into Diabetic Complications, Current Pharmaceutical Design 2004; 10 (29) . https://dx.doi.org/10.2174/1381612043382792
DOI https://dx.doi.org/10.2174/1381612043382792 |
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
-
RAGE and its Ligands in Retinal Disease
Current Molecular Medicine Intestinal Dysbiosis, Gut Hyperpermeability and Bacterial Translocation: Missing Links Between Depression, Obesity and Type 2 Diabetes
Current Pharmaceutical Design Group I Metabotropic Glutamate Receptor Signalling and its Implication in Neurological Disease
CNS & Neurological Disorders - Drug Targets Neuroprotection for Amyotrophic Lateral Sclerosis: Role of Stem Cells, Growth Factors, and Gene Therapy
Central Nervous System Agents in Medicinal Chemistry Human Embryonic Stem Cell Therapies for Neurodegenerative Diseases
CNS & Neurological Disorders - Drug Targets Flow Cytometry Study of Leukocyte Function: Analytical Comparison of Methods and their Applicability to Clinical Research
Current Medicinal Chemistry Neuro-Inflammatory Mechanisms in Developmental Disorders Associated with Intellectual Disability and Autism Spectrum Disorder: A Neuro- Immune Perspective
CNS & Neurological Disorders - Drug Targets Mitochondrial Disturbances, Tryptophan Metabolites and Neurodegeneration: Medicinal Chemistry Aspects
Current Medicinal Chemistry Poly(ADP-Ribose) Polymerase Inhibitors: New Pharmacological Functions and Potential Clinical Implications
Current Pharmaceutical Design Destination Penis? Gene Therapy as a Possible Treatment for Erectile Dysfunction
Current Gene Therapy Molecular Mechanisms and Therapeutic Application of NSAIDs and Derived Compounds in Alzheimers Disease
Current Alzheimer Research Editorial [Hot Topic: Galectin-1 as an Essential Factor in Nervous System (Guest Editor: Hidenori Horie)]
Current Drug Targets Interindividual Variability in the Efficacy of Oral Antiplatelet Drugs: Definitions, Mechanisms and Clinical Importance
Current Pharmaceutical Design Proteoglycans and Diabetes
Current Pharmaceutical Design Transforming Cytosolic Proteins into “Insoluble” and Membrane-toxic Forms Triggering Diseases/Aging by Genetic, Pathological or Environmental Factors
Protein & Peptide Letters Progress in Imaging Agents of Cell Apoptosis
Anti-Cancer Agents in Medicinal Chemistry Clinical Management of Diabetes Mellitus in the Older Adult Patient
Current Diabetes Reviews Chemical and Pharmacological Aspects of Heteroaryl-Nitrones
Current Medicinal Chemistry Gliclazide, Inflammation and Atherosclerosis
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Neurokinin Peptides and Neurokinin Receptors as Potential Therapeutic Intervention Targets of Basal Ganglia in the Prevention and Treatment of Parkinsons Disease
Current Drug Targets