Memantine prevents acute radiation-induced toxicities at hippocampal excitatory synapses
| العنوان: | Memantine prevents acute radiation-induced toxicities at hippocampal excitatory synapses |
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| المؤلفون: | Vasilis C. Mavratsas, Wei Zhou, Susan L. McGovern, Joseph G. Duman, Henry Cham, Shalaka Mulherkar, Matea Pavešković, Jeffrey Dinh, Kimberley F. Tolias, David R. Grosshans |
| المصدر: | Neuro-Oncology. 20:655-665 |
| بيانات النشر: | Oxford University Press (OUP), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Cancer Research, Dendritic spine, Dendritic Spines, Vesicular glutamate transporter 1, Pharmacology, Abnormalities, Radiation-Induced, Hippocampus, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Memantine, Postsynaptic potential, medicine, Animals, Rats, Long-Evans, Glutamate receptor antagonist, Cells, Cultured, biology, Glutamate receptor, Rats, Oncology, chemistry, Gamma Rays, 030220 oncology & carcinogenesis, Synapses, Basic and Translational Investigations, biology.protein, Excitatory postsynaptic potential, Neurology (clinical), Excitatory Amino Acid Antagonists, Postsynaptic density, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | Background Memantine has shown clinical utility in preventing radiation-induced cognitive impairment, but the mechanisms underlying its protective effects remain unknown. We hypothesized that abnormal glutamate signaling causes radiation-induced abnormalities in neuronal structure and that memantine prevents synaptic toxicity. Methods Hippocampal cultures expressing enhanced green fluorescent protein were irradiated or sham-treated and their dendritic spine morphology assessed at acute (minutes) and later (days) times using high-resolution confocal microscopy. Excitatory synapses, defined by co-localization of the pre- and postsynaptic markers vesicular glutamate transporter 1 and postsynaptic density protein 95, were also analyzed. Neurons were pretreated with vehicle, the N-methyl-d-aspartate-type glutamate receptor antagonist memantine, or the glutamate scavenger glutamate pyruvate transaminase to assess glutamate signaling. For animal studies, Thy-1-YFP mice were treated with whole-brain radiotherapy or sham with or without memantine. Results Unlike previously reported long-term losses of dendritic spines, we found that the acute response to radiation is an initial increase in spines and excitatory synapses followed by a decrease in spine/synapse density with altered spine dynamics. Memantine pre-administration prevented this radiation-induced synaptic remodeling. Conclusion These results demonstrate that radiation causes rapid, dynamic changes in synaptic structural plasticity, implicate abnormal glutamate signaling in cognitive dysfunction following brain irradiation, and describe a protective mechanism of memantine. |
| تدمد: | 1523-5866 1522-8517 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5af53410766cd23c63ff0181e47bb8de https://doi.org/10.1093/neuonc/nox203 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....5af53410766cd23c63ff0181e47bb8de |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15235866 15228517 |
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