Epicortical brevetoxin treatment promotes neural repair and functional recovery after ischemic stroke

Erica Sequeira, Marsha L. Pierce, Dina Akasheh, Stacey Sellers, William H. Gerwick, Daniel G. Baden, Thomas F. Murray

Research output: Contribution to journalArticle

Abstract

Emerging literature suggests that after a stroke, the peri-infarct region exhibits dynamic changes in excitability. In rodent stroke models, treatments that enhance excitability in the peri-infarct cerebral cortex promote motor recovery. This increase in cortical excitability and plasticity is opposed by increases in tonic GABAergic inhibition in the peri-infarct zone beginning three days after a stroke in a mouse model. Maintenance of a favorable excitatory-inhibitory balance promoting cerebrocortical excitability could potentially improve recovery. Brevetoxin-2 (PbTx-2) is a voltage-gated sodium channel (VGSC) gating modifier that increases intracellular sodium ([Na+]i), upregulates N-methyl-D-aspartate receptor (NMDAR) channel activity and engages downstream calcium (Ca2+) signaling pathways. In immature cerebrocortical neurons, PbTx-2 promoted neuronal structural plasticity by increasing neurite outgrowth, dendritogenesis and synaptogenesis. We hypothesized that PbTx-2 may promote excitability and structural remodeling in the peri-infarct region, leading to improved functional outcomes following a stroke. We tested this hypothesis using epicortical application of PbTx-2 after a photothrombotic stroke in mice. We show that PbTx-2 enhanced the dendritic arborization and synapse density of cortical layer V pyramidal neurons in the peri-infarct cortex. PbTx-2 also produced a robust improvement of motor recovery. These results suggest a novel pharmacologic approach to mimic activity-dependent recovery from stroke.

Original languageEnglish (US)
Article number374
JournalMarine Drugs
Volume18
Issue number7
DOIs
StatePublished - Jul 21 2020

All Science Journal Classification (ASJC) codes

  • Drug Discovery

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    Sequeira, E., Pierce, M. L., Akasheh, D., Sellers, S., Gerwick, W. H., Baden, D. G., & Murray, T. F. (2020). Epicortical brevetoxin treatment promotes neural repair and functional recovery after ischemic stroke. Marine Drugs, 18(7), [374]. https://doi.org/10.3390/MD18070374