The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of Schizophrenia
Schizophrenia (SZ) is a heterogeneous mental disorder, affecting ~1% of the worldwide population. One of the main pathophysiological theories of SZ is the imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr)....
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1022 |
| _version_ | 1797441605763858432 |
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| author | Nina Treder Albert Martínez-Pinteño Natalia Rodríguez Néstor Arbelo Santiago Madero Marta Gómez Clemente García-Rizo Sergi Mas Patricia Gassó Eduard Parellada Constanza Morén |
| author_facet | Nina Treder Albert Martínez-Pinteño Natalia Rodríguez Néstor Arbelo Santiago Madero Marta Gómez Clemente García-Rizo Sergi Mas Patricia Gassó Eduard Parellada Constanza Morén |
| author_sort | Nina Treder |
| collection | DOAJ |
| description | Schizophrenia (SZ) is a heterogeneous mental disorder, affecting ~1% of the worldwide population. One of the main pathophysiological theories of SZ is the imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr). This may lead to local glutamate storms coupled with excessive dendritic pruning and subsequent cellular stress, including nitrosative stress, during a critical period of neurodevelopment, such as adolescence. Nitrosative stress is mediated by nitric oxide (NO), which is released by NO synthases (NOS) and has emerged as a key signaling molecule implicated in SZ. Regarding glutamatergic models of SZ, the administration of NMDAr antagonists has been found to increase NOS levels in the prefrontal cortex (PFC) and ventral hippocampus (HPC). We hypothesized that suboptimal NOS function in adolescence could be a target for early treatments, including clozapine (CLZ) and the novel metabotropic glutamate receptor modulator JNJ-46356479 (JNJ). We analyzed the protein levels of NOS isoforms in adult PFC and HPC of a postnatal ketamine induced murine model of SZ receiving CLZ or JNJ during adolescence by western blot. Endothelial NOS and neuronal NOS increased under ketamine administration in PFC and decreased in CLZ or JNJ treatments. The same trends were found in the HPC in neuronal NOS. In contrast, inducible NOS was increased under JNJ treatment with respect to ketamine induction in the HPC, and the same trends were found in the PFC. Taken together, our findings suggest a misbalance of the NOS system following NMDAr antagonist administration, which was then modulated under early CLZ and JNJ treatments. |
| first_indexed | 2024-03-09T12:26:34Z |
| format | Article |
| id | doaj.art-39a2384a694d43dfb3f1d13b297759ce |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:26:34Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-39a2384a694d43dfb3f1d13b297759ce2023-11-30T22:34:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242102210.3390/ijms24021022The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of SchizophreniaNina Treder0Albert Martínez-Pinteño1Natalia Rodríguez2Néstor Arbelo3Santiago Madero4Marta Gómez5Clemente García-Rizo6Sergi Mas7Patricia Gassó8Eduard Parellada9Constanza Morén10Faculty of Psychology and Neuroscience, Maastricht University, 6211 LK Maastricht, The NetherlandsPharmacology Unit, Department of Basic and Clinical Practice, University of Barcelona, 08036 Barcelona, SpainPharmacology Unit, Department of Basic and Clinical Practice, University of Barcelona, 08036 Barcelona, SpainBarcelona Clínic Schizophrenia Unit, Institute of Neuroscience, Hospital Clínic of Barcelona, 08036 Barcelona, SpainClinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, SpainClinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, SpainBarcelona Clínic Schizophrenia Unit, Institute of Neuroscience, Hospital Clínic of Barcelona, 08036 Barcelona, SpainPharmacology Unit, Department of Basic and Clinical Practice, University of Barcelona, 08036 Barcelona, SpainPharmacology Unit, Department of Basic and Clinical Practice, University of Barcelona, 08036 Barcelona, SpainClinical and Experimental Neuroscience Area, The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, SpainPharmacology Unit, Department of Basic and Clinical Practice, University of Barcelona, 08036 Barcelona, SpainSchizophrenia (SZ) is a heterogeneous mental disorder, affecting ~1% of the worldwide population. One of the main pathophysiological theories of SZ is the imbalance of excitatory glutamatergic pyramidal neurons and inhibitory GABAergic interneurons, involving N-methyl-D-aspartate receptors (NMDAr). This may lead to local glutamate storms coupled with excessive dendritic pruning and subsequent cellular stress, including nitrosative stress, during a critical period of neurodevelopment, such as adolescence. Nitrosative stress is mediated by nitric oxide (NO), which is released by NO synthases (NOS) and has emerged as a key signaling molecule implicated in SZ. Regarding glutamatergic models of SZ, the administration of NMDAr antagonists has been found to increase NOS levels in the prefrontal cortex (PFC) and ventral hippocampus (HPC). We hypothesized that suboptimal NOS function in adolescence could be a target for early treatments, including clozapine (CLZ) and the novel metabotropic glutamate receptor modulator JNJ-46356479 (JNJ). We analyzed the protein levels of NOS isoforms in adult PFC and HPC of a postnatal ketamine induced murine model of SZ receiving CLZ or JNJ during adolescence by western blot. Endothelial NOS and neuronal NOS increased under ketamine administration in PFC and decreased in CLZ or JNJ treatments. The same trends were found in the HPC in neuronal NOS. In contrast, inducible NOS was increased under JNJ treatment with respect to ketamine induction in the HPC, and the same trends were found in the PFC. Taken together, our findings suggest a misbalance of the NOS system following NMDAr antagonist administration, which was then modulated under early CLZ and JNJ treatments.https://www.mdpi.com/1422-0067/24/2/1022clozapineglutamate metabotropic modulatorketaminenitrosative stressschizophrenia |
| spellingShingle | Nina Treder Albert Martínez-Pinteño Natalia Rodríguez Néstor Arbelo Santiago Madero Marta Gómez Clemente García-Rizo Sergi Mas Patricia Gassó Eduard Parellada Constanza Morén The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of Schizophrenia International Journal of Molecular Sciences clozapine glutamate metabotropic modulator ketamine nitrosative stress schizophrenia |
| title | The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of Schizophrenia |
| title_full | The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of Schizophrenia |
| title_fullStr | The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of Schizophrenia |
| title_full_unstemmed | The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of Schizophrenia |
| title_short | The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of Schizophrenia |
| title_sort | effect of clozapine and novel glutamate modulator jnj 46356479 on nitrosative stress in a postnatal murine ketamine model of schizophrenia |
| topic | clozapine glutamate metabotropic modulator ketamine nitrosative stress schizophrenia |
| url | https://www.mdpi.com/1422-0067/24/2/1022 |
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