Marine Neurotoxins | 2021
Neurotoxic: Ciguatoxin and brevetoxin—From excitotoxicity to neurotherapeutics
Abstract
Abstract Brevetoxins and ciguatoxins are lipid-soluble polyether marine natural products that produce, respectively, neurotoxic shellfish poisoning and Ciguatera in humans. They bind to voltage-gated sodium channels at neurotoxin site 5 in a mutually exclusive manner. This binding modifies the gating properties of sodium channels leading to depolarization of neurons. While both ciguatoxins and brevetoxins produce membrane depolarization, Pacific ciguatoxin produces a prolongation of action potentials and afterhyperpolarization that is likely due to a blockade of voltage-gated K+ channels. Using primary cultures of cerebellar granule cells we have demonstrated that both brevetoxin and ciguatoxin produce excitotoxicity with Caribbean ciguatoxin displaying high potency. The ability of gating modifiers of sodium channels to trigger sodium influx can also be assessed using the Na+-sensitive fluorescent dye, sodium-binding benzofuran isophthalate. Murine neocortical neurons in primary culture were used to demonstrate that the brevetoxin PbTx-1 is a full agonist while PbTx-2 and -3 have somewhat lower efficacies. The increment in neuronal [Na+]i exceeded 40\xa0mM at high concentrations of brevetoxins. Intracellular [Na+] increments have been demonstrated to increase NMDA receptor-mediated whole-cell currents and we have explored the ability of brevetoxin to augment NMDA receptor function. Brevetoxin treatment was found to increase both the mean open time and open probability of NMDA receptors. In addition brevetoxin enhanced cerebrocortical neuron neurite outgrowth, dendritic arbor complexity, dendritic filopodia density and synaptic density. Given these actions of brevetoxin in vitro, we used a photothrombotic stroke model in adult thy1-YFP mice to assess the effects of brevetoxin on structural plasticity and functional recovery following a unilateral stroke. Epicortical brevetoxin treatment enhanced dendritic arborization and synapse density of cortical layer V pyramidal neurons in the peri-infarct cortex. Brevetoxin also produced a robust improvement of motor recovery. These results suggest that brevetoxin may represent a novel pharmacologic approach to augment activity-dependent recovery from a stroke.