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 |

- Author Guidelines
- Bentham Author Support Services (BASS)
- 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
-
CORM-3 Regulates Microglia Activity, Prevents Neuronal Injury, and Improves Memory Function During Radiation-induced Brain Injury
Current Neurovascular Research Pharmacological Histone Deacetylation Distinguishes Transcriptional Regulators
Current Topics in Medicinal Chemistry Possible Exploitation of Non-Neuronal and Non-Chemical Synaptic Signalling Pathways in Epilepsy Therapy
Current Signal Transduction Therapy The Importance of NAD in Multiple Sclerosis
Current Pharmaceutical Design Therapeutic Targeting of CPT-11 Induced Diarrhea: A Case for Prophylaxis
Current Drug Targets Preserving Brain Function During Development and Aging with Erythropoietin
Current Neurovascular Research Novel Piperazinyl Derivatives with Anti-Hyperalgesic, Anti-Allodynic and Anti-Inflammatory activities Useful for the Treatment of Neuropathic Pain
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Interleukin-1 Drives Cerebrovascular Inflammation via MAP Kinase-Independent Pathways
Current Neurovascular Research Iron Overload is Associated with Perihematoma Edema Growth Following Intracerebral Hemorrhage that may Contribute to In-hospital Mortality and Long-term Functional Outcome
Current Neurovascular Research The Guanylyl Cyclase Inhibition by MB as Vasoplegic Circulatory Shock Therapeutical Target
Current Drug Targets Natural Products Towards the Discovery of Potential Future Antithrombotic Drugs
Current Pharmaceutical Design New Kid on the Block: Does Histamine Get Along with Inflammation in Amyotrophic Lateral Sclerosis?
CNS & Neurological Disorders - Drug Targets Calcium Metabolism and Oxidative Stress in Bone Fractures: Role of Antioxidants
Current Drug Metabolism The Evolution of Population Pharmacokinetic Model of Oral Phenytoin for Early Seizure Prophylaxis Post-Craniotomy
Current Drug Metabolism Functional Biomarkers: an Approach to Bridge Pharmacokinetics and Pharmacodynamics in Pediatric Clinical Trials
Current Pharmaceutical Design Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders
Current Neuropharmacology Acute Symptomatic Seizures in Geriatric Patients with Multiple Risk Factors - A Diagnostic Challenge
Current Aging Science Cerebrovascular Ultrasonography for Selecting Patients for Stroke Intervention
Recent Patents on CNS Drug Discovery (Discontinued) Hypertension in Pregnancy: Pathophysiology & Management Strategies
Current Pharmaceutical Design Pathophysiology of Patent Ductus Arteriosus in the Preterm Infant
Current Pediatric Reviews