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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.
Highlights
Ischemic stroke is a common neurological disorder and major cause of long-term disability worldwide [1]
We investigated the effect of potentially improve recovery. Brevetoxin-2 (PbTx-2) on neuroplasticity in the peri-infarct cortex and associated motor functions in a murine model of stroke
The main findings of this study are: 1. epicortical application of PbTx-2 at the stroke site produced a 2-fold increase in dendritic arborization and increased synaptogenesis in the peri-infarct cortex, 2. photothrombotic stroke in the forelimb motor cortex produced functional deficits that were confined to the digits of the paw, 3
Summary
Ischemic stroke is a common neurological disorder and major cause of long-term disability worldwide [1]. Tissue plasminogen activator (tPA) is the only FDA-approved pharmacologic treatment for ischemic or thrombotic stroke, which carries the risk of producing an intracerebral hemorrhage [2,3,4]. This pharmacologic advancement of acute care has resulted in a decline in mortality rate, it has produced a greater number of disabled survivors. Neuronal circuits do undergo limited re-mapping and reorganization after stroke, and these repair processes are associated with neurogenesis, dentritogenesis, synaptogenesis, axonal sprouting and Previous work has suggested parallels between plasticity mechanisms in the developing brain and those occurring in the adult brain after a stroke event [6,7,8,9,10].
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