Abstract
A significant number of laboratories observed that poly (ADP-ribose) polymerase (PARP) inhibitors, administered a few hours after ischemic or traumatic brain injury, may drastically reduce the subsequent neurological damage. It has also been shown that PARP inhibitors, administered for 24 hours to rats with permanent middle cerebral artery occlusion (MCAO), may reduce the number of dying neurons for a long period after surgery, thus suggesting that these agents could reduce the delayed brain damage and the neurological and cognitive impairment (dementia) frequently observed a few months after a stroke. In organotypic hippocampal slices exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG), an alkylating agent able to activate PARP, a selective and delayed degeneration of the CA1 pyramidal cells which was anatomically similar to that observed after a short period of oxygen and glucose deprivation (OGD) has been described. Biochemical and electrophysiological approaches showed that MNNG exposure caused an increased expression and function of the calcium permeable α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) channels in the CA1 but not in the CA3 hippocampal region. PARP inhibitors prevented this increase and reduced CA1 cell death. The AMPA receptor antagonist 2,3-dihydroxy-6- nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione or the selective Ca2+ permeable AMPA channel blocker 1-Naphthyl acetyl spermine (NASPM), also reduced the MNNG-induced CA1 pyramidal cell death. Since activation of PARP-1 facilitate the expression of Ca2+ permeable channels and the subsequent delayed cell death, PARP inhibitors administered a few hours after a stroke may not only reduce the early post-ischemic brain damage but also the late neuronal death frequently occurring after severe stroke.
Keywords: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, cell death, Dementia, Neuroprotection, Poly(ADP-ribose) polymerases, stroke.
CNS & Neurological Disorders - Drug Targets
Title:Poly(ADP-Ribose)Polymerase 1 (PARP-1) Activation and Ca2+ Permeable α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Channels in Post-Ischemic Brain Damage: New Therapeutic Opportunities?
Volume: 14 Issue: 5
Author(s): Elisabetta Gerace, Domenico E. Pellegrini-Giampietro, Flavio Moroni and Guido Mannaioni
Affiliation:
Keywords: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, cell death, Dementia, Neuroprotection, Poly(ADP-ribose) polymerases, stroke.
Abstract: A significant number of laboratories observed that poly (ADP-ribose) polymerase (PARP) inhibitors, administered a few hours after ischemic or traumatic brain injury, may drastically reduce the subsequent neurological damage. It has also been shown that PARP inhibitors, administered for 24 hours to rats with permanent middle cerebral artery occlusion (MCAO), may reduce the number of dying neurons for a long period after surgery, thus suggesting that these agents could reduce the delayed brain damage and the neurological and cognitive impairment (dementia) frequently observed a few months after a stroke. In organotypic hippocampal slices exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG), an alkylating agent able to activate PARP, a selective and delayed degeneration of the CA1 pyramidal cells which was anatomically similar to that observed after a short period of oxygen and glucose deprivation (OGD) has been described. Biochemical and electrophysiological approaches showed that MNNG exposure caused an increased expression and function of the calcium permeable α-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) channels in the CA1 but not in the CA3 hippocampal region. PARP inhibitors prevented this increase and reduced CA1 cell death. The AMPA receptor antagonist 2,3-dihydroxy-6- nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione or the selective Ca2+ permeable AMPA channel blocker 1-Naphthyl acetyl spermine (NASPM), also reduced the MNNG-induced CA1 pyramidal cell death. Since activation of PARP-1 facilitate the expression of Ca2+ permeable channels and the subsequent delayed cell death, PARP inhibitors administered a few hours after a stroke may not only reduce the early post-ischemic brain damage but also the late neuronal death frequently occurring after severe stroke.
Export Options
About this article
Cite this article as:
Gerace Elisabetta, Pellegrini-Giampietro E. Domenico, Moroni Flavio and Mannaioni Guido, Poly(ADP-Ribose)Polymerase 1 (PARP-1) Activation and Ca2+ Permeable α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid (AMPA) Channels in Post-Ischemic Brain Damage: New Therapeutic Opportunities?, CNS & Neurological Disorders - Drug Targets 2015; 14 (5) . https://dx.doi.org/10.2174/1871527314666150430162841
DOI https://dx.doi.org/10.2174/1871527314666150430162841 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...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
Related Articles
-
A Comprehensive Review of Alzheimer’s Association with Related Proteins: Pathological Role and Therapeutic Significance
Current Neuropharmacology Clinical Applicability of Conditioning Techniques in Ischemia-Reperfusion Injury: A Review of the Literature
Current Cardiology Reviews Aβ Oligomers Induce Glutamate Release from Hippocampal Neurons
Current Alzheimer Research Effects of the Novel Non-Peptidyl Low Molecular Weight Radical Scavenger IAC in Different Models of Inflammation: A New Perspective in Anti-Inflammatory Therapy
Current Medicinal Chemistry Drug Withdrawal and Hyperphagia: Lessons from Tobacco and Other Drugs
Current Pharmaceutical Design Sepsis in the Central Nervous System and Antioxidant Strategies with Nacetylcysteine, Vitamins and Statins
Current Neurovascular Research Toxic Metals in Herbal Medicines. A Review
Current Bioactive Compounds Non-steroidal Anti-Inflammatory Drugs and Melanoma
Current Pharmaceutical Design Lipoxin and Synthetic Lipoxin Analogs: An Overview of Anti- Inflammatory Functions and New Concepts in Immunomodulation
Inflammation & Allergy - Drug Targets (Discontinued) Molecules to Selectively Target Receptors for Treatment of Pain and Neurogenic Inflammation
Recent Patents on Inflammation & Allergy Drug Discovery Strategies to Convert PACAP from a Hypophysiotropic Neurohormone Into a Neuroprotective Drug
Current Pharmaceutical Design The Effects and Underlying Mechanisms of Cell Therapy on Blood-Brain Barrier Integrity After Ischemic Stroke
Current Neuropharmacology Traumatic Brain Injury as a Risk Factor for Alzheimer’s Disease: Is Inflammatory Signaling a Key Player?
Current Alzheimer Research Postischemic-Anoxic Encephalopathy After Global Forebrain Ischemia
Central Nervous System Agents in Medicinal Chemistry Stroke-Induced Neurogenesis: Physiopathology and Mechanisms
Current Neurovascular Research PDGF Receptor β Signaling in Pericytes Following Ischemic Brain Injury
Current Neurovascular Research Recombinant Tissue-Type Plasminogen Activator (Alteplase) in the Management of Acute Ischemic Stroke: A Review of its Pharmacological Properties, Efficacy, Safety and Pharmacoeconomic Aspects
Current Drug Therapy Granulocyte Colony-Stimulating Factor Attenuates Blood-Brain Barrier Damage and Improves Cognitive Function in Spontaneously Hypertensive Rats
CNS & Neurological Disorders - Drug Targets PPARγ: Potential Therapeutic Target for Ailments Beyond Diabetes and its Natural Agonism
Current Drug Targets Therapeutic Indications and Action Mechanisms of Bilirubin: Suggestions from Natural Calculus Bovis
Current Signal Transduction Therapy