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

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.

Marine natural products

“…This yet again reinforces that the effects of highly potent bioactive molecules can potentially be clinically benecial when used below toxic doses. 354 The acute toxicity of 44-methylgambierone, a member of the ciguatera-causing Gambierdiscus toxins, was assessed and it was found to have an LD 50 in the 20-28 mg kg À1 range, a low level of toxicity. An assessment of 90 microalgal species (252 isolates within 32 genera over seven classes) using LCMS found that all eight Gambierdiscus spp.…”

“…This yet again reinforces that the effects of highly potent bioactive molecules can potentially be clinically beneficial when used below toxic doses. 354…”

Voltage-Gated Sodium Channels: A Prominent Target of Marine Toxins

“…A recent study has demonstrated that BTX-2 improved synapse density and dendritic arborization and of cortical layer V pyramidal neurons in the peri-infarct cortex in mice after a photothrombotic stroke. In addition, BTX-2 resulted in a significant amelioration in motor recovery [ 90 ].…”

Industrial Applications of Dinoflagellate Phycotoxins Based on Their Modes of Action: A Review

“…Sequeira et al [ 134 ] reported that PbTx treatment in mice decreased the percentage of foot faults with a two-fold increase in dendritic arbor complexity. Additionally, they reported that PbTx-2 enhanced the dendritic arborization and synapse density of the cortical layer V pyramidal neurons in the peri-infarct cortex and improved motor recovery [ 135 ]. These results demonstrate that PbTx could be a potential candidate for the development of post-stroke recovery drugs.…”