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Memantine Improves Recovery After Spreading Depolarization in Brain Slices and can be Considered for Future Clinical Trials

  • Spreading cortical depolarization
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Abstract

Background

Spreading depolarization (SD) has been identified as a key mediator of secondary lesion progression after acute brain injuries, and clinical studies are beginning to pharmacologically target SDs. Although initial work has focused on the N-Methyl-D-aspartate receptor antagonist ketamine, there is also interest in alternatives that may be better tolerated. We recently showed that ketamine can inhibit mechanisms linked to deleterious consequences of SD in brain slices. The present study tested the hypothesis that memantine improves recovery of brain slices after SD and explored the effects of memantine in a clinical case targeting SD.

Methods

For mechanistic studies, electrophysiological and optical recordings were made from hippocampal area CA1 in acutely prepared brain slices from mice. SDs were initiated by localized microinjection of K+ in conditions of either normal or reduced metabolic substrate availability. Memantine effects were assessed from intrinsic optical signals and extracellular potential recordings. For the clinical report, a subdural strip electrode was used for continuous electrocorticographic recording after the surgical evacuation of a chronic subdural hematoma.

Results

In brain slice studies, memantine (10–300 µM) did not prevent the initiation of SD, but impaired SD propagation rate and recovery from SD. Memantine reduced direct current (DC) shift duration and improved recovery of synaptic potentials after SD. In brain slices with reduced metabolic substrate availability, memantine reduced the evidence of structural disruption after the passage of SD. In our clinical case, memantine did not noticeably immediately suppress SD; however, it was associated with a significant reduction of SD duration and a reduction in the electrocorticographic (ECoG) suppression that occurs after SD. SD was completely suppressed, with improvement in neurological examination with the addition of a brief course of ketamine.

Conclusions

These data extend recent work showing that N-Methyl-D-aspartate receptor antagonists can improve recovery from SD. These results suggest that memantine could be considered for future clinical trials targeting SD, and in some cases as an adjunct or alternative to ketamine.

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Funding

Supported by National Institutes of Health Grants NS106901, GM109089, T32 HL007736, NS102978, NS104742.

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Authors and Affiliations

  1. Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA

    Katelyn M. Reinhart, Alanna Humphrey & C. William Shuttleworth

  2. Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA

    Katelyn M. Reinhart & K. C. Brennan

  3. Department of Neurosurgery, University of New Mexico School of Medicine, Albuquerque, NM, USA

    Andrew P. Carlson

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Contributions

KMR: Experimental design, acquisition and interpretation of data, and drafting and revision of article. AH: Experimental design, acquisition and analysis of data, and revising article. KCB: Conception, design, and critically revising article. APC: Conception and design, acquisition and interpretation of data, and drafting and revision of article. CWS: Conception and design, interpretation and analysis of data, and drafting and critically revising article. The final manuscript was approved by all authors.

Corresponding author

Correspondence to C. William Shuttleworth.

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Conflicts of Interest

Drs. Shuttleworth, Reinhart, Brennan and Carlson report receiving grants from the National Institutes of Health during the conduct of the study. NS106901 (Shuttleworth), T32 HL007736 (Reinhart), GM109089 (Carlson), NS102978, NS104742 (Brennan). There are no other conflicts of interest to declare.

Human and Animal Rights

We confirm that the research reported here adheres to ethical guidelines, with animal procedures for preparation of in vitro brain slices being approved by the University of New Mexico Health Sciences Center Institutional Animal Care and Use Committee (protocol # 19-200973-HSC), and the example of clinical monitoring was approved by prospective informed consent under local institutional review board (protocol # UNM HRPO #17-297).

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Reinhart, K.M., Humphrey, A., Brennan, K.C. et al. Memantine Improves Recovery After Spreading Depolarization in Brain Slices and can be Considered for Future Clinical Trials. Neurocrit Care 35 (Suppl 2), 135–145 (2021). https://doi.org/10.1007/s12028-021-01351-9

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