title: PARP-1 activation causes neuronal death in the hippocampal CA1 region by increasing the expression of Ca(2+)-permeable AMPA receptors.
abstract: An excessive activation of poly(ADP-ribose) polymerases (PARPs) may trigger a form of neuronal death similar to that occurring in neurodegenerative disorders. To investigate this process, we exposed organotypic hippocampal slices to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG, 100μM for 5min), an alkylating agent widely used to activate PARP-1. MNNG induced a pattern of degeneration of the CA1 pyramidal cells morphologically similar to that observed after a brief period of oxygen and glucose deprivation (OGD). MNNG exposure was also associated with a dramatic increase in PARP-activity and a robust decrease in NAD(+) and ATP content. These effects were prevented by PARP-1 but not PARP-2 inhibitors. In our experimental conditions, cell death was not mediated by AIF translocation (parthanatos) or caspase-dependent apoptotic processes. Furthermore, we found that PARP activation was followed by a significant deterioration of neuronal membrane properties. Using electrophysiological recordings we firstly investigated the suggested ability of ADP-ribose to open TRPM2 channels in MNNG-induced cells death, but the results we obtained showed that TRPM2 channels are not involved. We then studied the involvement of glutamate receptor-ion channel complex and we found that NBQX, a selective AMPA receptor antagonist, was able to effectively prevent CA1 neuronal loss while MK801, a NMDA antagonist, was not active. Moreover, we observed that MNNG treatment increased the ratio of GluA1/GluA2 AMPAR subunit expression, which was associated with an inward rectification of the IV relationship of AMPA sEPSCs in the CA1 but not in the CA3 subfield. Accordingly, 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca(2+)-permeable GluA2-lacking AMPA receptors, reduced MNNG-induced CA1 pyramidal cell death. In conclusion, our results show that activation of the nuclear enzyme PARP-1 may change the expression of membrane proteins and Ca(2+) permeability of AMPA channels, thus affecting the function and survival of CA1 pyramidal cells.
authors: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors: E
authors: E
authors: Gerace
authors: Department of Neuroscience, Section of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors: A
authors: A
authors: Masi
authors: Department of Neuroscience, Section of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors: F
authors: F
authors: Resta
authors: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors: R
authors: R
authors: Felici
authors: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors: E
authors: E
authors: Landucci
authors: Department of Experimental and Biomedical Sciences, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors: T
authors: T
authors: Mello
authors: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors: D E
authors: DE
authors: Pellegrini-Giampietro
authors: Department of Neuroscience, Section of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors: G
authors: G
authors: Mannaioni
authors: Department of Neuroscience, Section of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Electronic address: flavio.moroni@unifi.it.
authors: F
authors: F
authors: Moroni
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D050053:TRPM Cation Channels; C557080:Trpm2 protein, rat; C499322:Parp1 protein, rat; C557783:Parp2 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D005947:Glucose; D002118:Calcium
keywords: Ca(2+)-permeable AMPA receptors; Cell death; GluA1; Hippocampus; MNNG; Organotypic hippocampal slices; PARP