Epicortical Brevetoxin Treatment Promotes Neural Repair and Functional Recovery after Ischemic Stroke

Mar Drugs. 2020 Jul 21;18(7):374. doi: 10.3390/md18070374.

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.

Keywords: brevetoxin; ischemic stroke; neuroplasticity; peri-infarct.

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Cerebral Cortex / physiopathology
  • Disease Models, Animal
  • Excitatory Amino Acid Agonists / administration & dosage*
  • Injections
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Marine Toxins / administration & dosage*
  • Mice, Transgenic
  • Motor Activity / drug effects*
  • Neuronal Plasticity / drug effects*
  • Oxocins / administration & dosage*
  • Recovery of Function
  • Thrombotic Stroke / drug therapy*
  • Thrombotic Stroke / metabolism
  • Thrombotic Stroke / pathology
  • Thrombotic Stroke / physiopathology

Substances

  • Bacterial Proteins
  • Excitatory Amino Acid Agonists
  • Luminescent Proteins
  • Marine Toxins
  • Oxocins
  • Ptychodiscus brevis T2 toxin
  • yellow fluorescent protein, Bacteria