Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus
We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (...
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8249 |
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| author | Ekaterina V. Pershina Irina Yu. Chernomorets Dmitry A. Fedorov Vladimir I. Arkhipov |
| author_facet | Ekaterina V. Pershina Irina Yu. Chernomorets Dmitry A. Fedorov Vladimir I. Arkhipov |
| author_sort | Ekaterina V. Pershina |
| collection | DOAJ |
| description | We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus. |
| first_indexed | 2024-03-11T04:16:11Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:16:11Z |
| publishDate | 2023-05-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6b9a0de067ee42039c29565ada07c98b2023-11-17T23:07:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249824910.3390/ijms24098249Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat HippocampusEkaterina V. Pershina0Irina Yu. Chernomorets1Dmitry A. Fedorov2Vladimir I. Arkhipov3Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, RussiaInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, RussiaInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, RussiaInstitute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, RussiaWe studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus.https://www.mdpi.com/1422-0067/24/9/8249neurodegenerationhippocampusexcitotoxicityneuroinflammationtrimethyltin (TMT)NMDArs |
| spellingShingle | Ekaterina V. Pershina Irina Yu. Chernomorets Dmitry A. Fedorov Vladimir I. Arkhipov Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus International Journal of Molecular Sciences neurodegeneration hippocampus excitotoxicity neuroinflammation trimethyltin (TMT) NMDArs |
| title | Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus |
| title_full | Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus |
| title_fullStr | Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus |
| title_full_unstemmed | Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus |
| title_short | Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus |
| title_sort | pharmacological modulation of excitotoxicity through the combined use of nmda receptor inhibition and group iii mglu activation reduces tmt induced neurodegeneration in the rat hippocampus |
| topic | neurodegeneration hippocampus excitotoxicity neuroinflammation trimethyltin (TMT) NMDArs |
| url | https://www.mdpi.com/1422-0067/24/9/8249 |
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