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Low-Intensity Ultrasound Decreases Ischemia-Induced Edema by Inhibiting N-Methyl-d-Aspartic Acid Receptors

  • Binika Hada (a1), Mrigendra Bir Karmacharya (a2), So R. Park (a2) and Byung H. Choi (a1)

Abstract

Background: We have previously shown that low-intensity ultrasound (LIUS), a noninvasive mechanical stimulus, inhibits brain edema formation induced by oxygen and glucose deprivation (OGD) or treatment with glutamate, a mediator of OGD-induced edema, in acute rat hippocampal slice model in vitro. Methods: In this study, we treated the rat hippocampal slices with N-methyl-d-aspartic acid (NMDA) or (S)-3,5-dihydroxyphenylglycine (DHPG) to determine whether these different glutamate receptor agonists induce edema. The hippocampal slices were then either sonicated with LIUS or treated with N-methyl-d-aspartic acid receptor (NMDAR) antagonists, namely, MK-801 and ketamine, and observed their effects on edema formation. Results: We observed that treatment with NMDA, an agonist of ionotropic glutamate receptors, induced brain edema at similar degrees compared with that induced by OGD. However, treatment with DHPG, an agonist of metabotropic glutamate receptors, did not significantly induce brain edema. Treatment with the NMDAR antagonists MK-801 or ketamine efficiently prevented brain edema formation by both OGD and NMDA in a concentration-dependent manner. N-Methyl-d-aspartic acid-induced brain edema was alleviated by LIUS in an intensity-dependent manner when ultrasound was administered at 30, 50, or 100 mW/cm2 for 20 minutes before the induction of the edema. Furthermore, LIUS reduced OGD- and NMDA-induced phosphorylation of NMDARs at Y1325. Conclusion: These results suggest that LIUS can inhibit OGD- or NMDA-induced NMDAR activation by preventing NMDAR phosphorylation, thereby reducing a subsequent brain edema formation. The mechanisms by which LIUS inhibits NMDAR phosphorylation need further investigation.

Des ultrasons de faible intensité peuvent réduire desœdèmescérébraux consécutifs à un AVC ischémique en inhibant l’action des récepteurs NMDA.Contexte: Comme nous l’avons montré précédemment dans le cas d’un modèle in vitro utilisant des coupes d’hippocampes de rats, des ultrasons de faible intensité, des stimuli mécaniques non-invasifs, peuvent inhiber la formation d’œdèmes au cerveau induits par la privation en apports d’oxygène et de glucose ou par un traitement au glutamate, ce dernier étant un médiateur des œdèmes induits par une telle privation. Méthodes: Dans la présente étude, nous avons soumis ces coupes à un traitement d’acide-N-méthyl-D-aspartique (NMDA) ou de (S)-3,5-dihydroxyphénylglycine (DHPG) afin de vérifier dans quelle mesure ces agonistes des récepteurs du glutamate pouvaient provoquer un œdème cérébral. À cet effet, nos coupes d’hippocampes de rats ont été soit soumises à des ultrasons de faible intensité ou ont fait l’objet d’un traitement avec des antagonistes affectant les récepteurs NMDA, à savoir le MK-801 et la kétamine. Nous avons ensuite évalué leurs effets respectifs en ce qui regarde la formation d’œdèmes. Résultats: Nous avons constaté qu’un traitement au NMDA, un agoniste des récepteurs ionotropiques du glutamate, provoquait, si on le compare à la privation en apports d’oxygène et de glucose, un œdème cérébral de sévérité comparable. Cela dit, un traitement mené avec le (S)-3,5-DHPG, un agoniste des récepteurs métabotropes du glutamate, n’a pas entraîné de façon significative des œdèmes cérébraux. En fonction de l’utilisation concentrations précises, des traitements au moyen du MK-801 ou de la kétamine ont par ailleurs prévenu de façon efficace l’apparition d’œdèmes cérébraux, peu importe si ces derniers étaient attribuables à une privation en apports d’oxygène et de glucose ou au NMDA. Les œdèmes cérébraux produits par le NMDA ont aussi été atténués pendant 20 minutes par des ultrasons à des niveaux spécifiques de faible intensité, soit 30, 50 ou 100 mW/cm2. Qui plus est, ces ultrasons ont permis de réduire la phosphorylation des récepteurs NMDA à Y1325. Conclusions: Ces résultats donnent à penser que des ultrasons de faible intensité peuvent inhiber l’activation des récepteurs NMDA produite par le NMDA et la privation en apports d’oxygène et de glucose en empêchant la phosphorylation des récepteurs NMDA, réduisant ainsi la formation d’autres œdèmes cérébraux. Mieux comprendre les mécanismes en vertu desquels les ultrasons de faible intensité inhibent la phosphorylation des récepteurs NMDA nécessitera néanmoins de plus amples travaux de recherche.

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Copyright

Corresponding author

Correspondence to: B. Hyune Choi, Department of Biomedical Sciences, Inha University College of Medicine, Incheon 400-103, Korea. Email: bryan@inha.ac.kr

References

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Keywords

Low-Intensity Ultrasound Decreases Ischemia-Induced Edema by Inhibiting N-Methyl-d-Aspartic Acid Receptors

  • Binika Hada (a1), Mrigendra Bir Karmacharya (a2), So R. Park (a2) and Byung H. Choi (a1)

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