Antillatoxin-Stimulated Neurite Outgrowth Involves the Brain-Derived Neurotrophic Factor (BDNF)-Tropomyosin Related Kinase B (TrkB) Signaling Pathway br

Voltage-gated sodium channel (VGSC) activators promote neurite outgrowth byaugmenting intracellular Na+concentration ([Na+]i) and upregulating N-methyl-D-aspartate receptor(NMDAR) function. NMDAR activation stimulates calcium (Ca2+)influx and increases brain-derivedneurotrophic factor (BDNF) release and activation of tropomyosin receptor kinase B (TrkB)signaling. The BDNF-TrkB pathway has been implicated in activity-dependent neuronaldevelopment. We have previously shown that antillatoxin (ATX), a novel lipopeptide isolatedfrom the cyanobacteriumMoorea producens, is a VGSC activator that produces an elevation of [Na+]i.Here we address the effect of ATX on the synthesis and release of BDNF and determine the signalingmechanisms by which ATX enhances neurite outgrowth in immature cerebrocortical neurons. ATXtreatment produced a concentration-dependent release of BDNF. Acute treatment with ATX alsoresulted in increased synthesis of BDNF. ATX stimulation of neurite outgrowth was prevented bypretreatment with a TrkB inhibitor or transfection with a dominant-negative Trk-B. The ATXactivation of TrkB and Akt was blocked by both a NMDAR antagonist (MK-801) and a VGSCblocker (tetrodotoxin). These results suggest that VGSC activators such as the structurally novelATX may represent a new pharmacological strategy to promote neuronal plasticity through a NMDAR-BDNF-TrkB-dependent mechanism