Sodium channel gating modifier promotes neuronal repair and functional recovery from ischemic stroke.

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Authors
Sequeira, Erica
Issue Date
2020-04-30
Type
Dissertation
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en_US
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Abstract
Ischemic stroke is a leading cause of adult disability, which presents a pressing need for a pharmacological therapy. Emerging literature suggests that after a stroke, the peri-infarct region exhibits dynamic changes in excitability. The acute ischemic phase triggers glutamate-mediated excitotoxic neuronal death. On the contrary, during the chronic phase, when the brain begins to repair itself, it displays heightened neuroplasticity that also resembles the neuronal developmental stages. However, this recovery is incomplete. Thus, promoting cortical excitability during the repair and recovery phase could potentially be therapeutic. Brevetoxin-2 (PbTx-2), a voltage-gated sodium channel (VGSC) modifier, increases intracellular sodium ([Na+]i), upregulates N-methyl-d-aspartate receptors (NMDAR) channel activity, and engages activity-dependent downstream calcium (Ca2+) signaling pathways. In immature cerebrocortical neurons, PbTx-2 promoted neuronal structural plasticity by increasing neurite outgrowth, dendritogenesis and synaptogenesis. This led us to hypothesize that PbTx-2 could promote structural remodeling of neural networks in the peri-infarct site and subsequently promote functional outcomes after stroke. In the current study, we have investigated this phenomenon using adult male transgenic yellow fluorescent protein expressing (YFP) mice by providing an epicortical application of PbTx-2 five days after inducing a photothrombotic stroke. We show that PbTx-2 enhanced dendritic arbor complexity and excitatory synapse density of the cortical layer V pyramidal neurons in the peri-infarct cortex. Consistent with increased neuronal plasticity, PbTx-2 also produced a robust gain of motor recovery. Collectively, our results identify an activity-dependent pharmacologic strategy to promote recovery from stroke and possibly other brain injuries.
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Creighton University
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Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
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