Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening
The disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN) has been observed early in several auditory pathologies (e.g., noise-induced or ototoxic drug-induced or age-related hearing loss)....
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MDPI AG
2024-01-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/13/2/149 |
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| author | Anissa Rym Saidia Florence François François Casas Ilana Mechaly Stéphanie Venteo Joseph T. Veechi Jérôme Ruel Jean-Luc Puel Jing Wang |
| author_facet | Anissa Rym Saidia Florence François François Casas Ilana Mechaly Stéphanie Venteo Joseph T. Veechi Jérôme Ruel Jean-Luc Puel Jing Wang |
| author_sort | Anissa Rym Saidia |
| collection | DOAJ |
| description | The disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN) has been observed early in several auditory pathologies (e.g., noise-induced or ototoxic drug-induced or age-related hearing loss). It has been suggested that glutamate excitotoxicity may be an inciting element in the degenerative cascade observed in these pathological cochlear conditions. Moreover, oxidative damage induced by free hydroxyl radicals and nitric oxide may dramatically enhance cochlear damage induced by glutamate excitotoxicity. To investigate the underlying molecular mechanisms involved in cochlear excitotoxicity, we examined the molecular basis responsible for kainic acid (KA, a full agonist of AMPA/KA-preferring glutamate receptors)-induced IHC synapse loss and degeneration of the terminals of the type I spiral ganglion afferent neurons using a cochlear explant culture from P3 mouse pups. Our results demonstrated that disruption of the synaptic connection between IHCs and SGNs induced increased levels of oxidative stress, as well as altered both mitochondrial function and neurotrophin signaling pathways. Additionally, the application of exogenous antioxidants and neurotrophins (NT3, BDNF, and small molecule TrkB agonists) clearly increases synaptogenesis. These results suggest that understanding the molecular pathways involved in cochlear excitotoxicity is of crucial importance for the future clinical trials of drug interventions for auditory synaptopathies. |
| first_indexed | 2024-03-07T22:44:20Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-07T22:44:20Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-2d39b64836784478ae6dc8b6e4031a8e2024-02-23T15:05:18ZengMDPI AGAntioxidants2076-39212024-01-0113214910.3390/antiox13020149Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules ScreeningAnissa Rym Saidia0Florence François1François Casas2Ilana Mechaly3Stéphanie Venteo4Joseph T. Veechi5Jérôme Ruel6Jean-Luc Puel7Jing Wang8Institute for Neurosciences of Montpellier (INM), INSERM U1298, University Montpellier, 34295 Montpellier, FranceInstitute for Neurosciences of Montpellier (INM), INSERM U1298, University Montpellier, 34295 Montpellier, FranceINRA, UMR 866 Dynamique Musculaire et Métabolisme, 34060 Montpellier, FranceInstitute for Neurosciences of Montpellier (INM), INSERM U1298, University Montpellier, 34295 Montpellier, FranceInstitute for Neurosciences of Montpellier (INM), INSERM U1298, University Montpellier, 34295 Montpellier, FranceInstitute for Neurosciences of Montpellier (INM), INSERM U1298, University Montpellier, 34295 Montpellier, FranceCentre de Recherche en CardioVasculaire et Nutrition, Aix-Marseille Université-INSERM, 1263-INRAE 1260, 13385 Marseille, FranceInstitute for Neurosciences of Montpellier (INM), INSERM U1298, University Montpellier, 34295 Montpellier, FranceInstitute for Neurosciences of Montpellier (INM), INSERM U1298, University Montpellier, 34295 Montpellier, FranceThe disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN) has been observed early in several auditory pathologies (e.g., noise-induced or ototoxic drug-induced or age-related hearing loss). It has been suggested that glutamate excitotoxicity may be an inciting element in the degenerative cascade observed in these pathological cochlear conditions. Moreover, oxidative damage induced by free hydroxyl radicals and nitric oxide may dramatically enhance cochlear damage induced by glutamate excitotoxicity. To investigate the underlying molecular mechanisms involved in cochlear excitotoxicity, we examined the molecular basis responsible for kainic acid (KA, a full agonist of AMPA/KA-preferring glutamate receptors)-induced IHC synapse loss and degeneration of the terminals of the type I spiral ganglion afferent neurons using a cochlear explant culture from P3 mouse pups. Our results demonstrated that disruption of the synaptic connection between IHCs and SGNs induced increased levels of oxidative stress, as well as altered both mitochondrial function and neurotrophin signaling pathways. Additionally, the application of exogenous antioxidants and neurotrophins (NT3, BDNF, and small molecule TrkB agonists) clearly increases synaptogenesis. These results suggest that understanding the molecular pathways involved in cochlear excitotoxicity is of crucial importance for the future clinical trials of drug interventions for auditory synaptopathies.https://www.mdpi.com/2076-3921/13/2/149synaptopathyglutamate excitotoxicitykainic acidAMPA receptorsoxidative stressantioxidants |
| spellingShingle | Anissa Rym Saidia Florence François François Casas Ilana Mechaly Stéphanie Venteo Joseph T. Veechi Jérôme Ruel Jean-Luc Puel Jing Wang Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening Antioxidants synaptopathy glutamate excitotoxicity kainic acid AMPA receptors oxidative stress antioxidants |
| title | Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening |
| title_full | Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening |
| title_fullStr | Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening |
| title_full_unstemmed | Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening |
| title_short | Oxidative Stress Plays an Important Role in Glutamatergic Excitotoxicity-Induced Cochlear Synaptopathy: Implication for Therapeutic Molecules Screening |
| title_sort | oxidative stress plays an important role in glutamatergic excitotoxicity induced cochlear synaptopathy implication for therapeutic molecules screening |
| topic | synaptopathy glutamate excitotoxicity kainic acid AMPA receptors oxidative stress antioxidants |
| url | https://www.mdpi.com/2076-3921/13/2/149 |
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