Abstract
The frequent occurrence of Moorea producens (formerly Lyngbya majuscula) blooms has been associated with adverse effects on human health. Hoiamide A is a structurally unique cyclic depsipeptide isolated from an assemblage of the marine cyanobacteria M. producens and Phormidium gracile. We examined the influence of hoiamide A on neurite outgrowth in neocortical neurons and found that it suppressed neurite outgrowth with an IC50 value of 4.89 nM. Further study demonstrated that hoiamide A stimulated lactic acid dehydrogenase (LDH) efflux, nuclear condensation and caspase-3 activity with EC50 values of 3.66, 2.55 and 4.33 nM, respectively. These data indicated that hoiamide A triggered a unique neuronal death profile that involves both necrotic and apoptotic mechanisms. The similar potencies and similar time-response relationships between LDH efflux and caspase-3 activation/nuclear condensation suggested that both necrosis and apoptosis may derive from interaction with a common molecular target. The broad-spectrum caspase inhibitor, Z-VAD-FMK completely inhibited hoiamide A-induced neurotoxicity. Additionally, hoiamide A stimulated JNK phosphorylation, and a JNK inhibitor attenuated hoiamide A-induced neurotoxicity. Collectively, these data demonstrate that hoiamide A-induced neuronal death requires both JNK and caspase signaling pathways. The potent neurotoxicity and unique neuronal cell death profile of hoiamide A represents a novel neurotoxic chemotype from marine cyanobacteria.
Highlights
Marine cyanobacteria are prolific producers of structurally novel and biologically active natural products and are especially rich in metabolites with toxic properties [1,2,3,4]
A at neurotoxin site 2 on voltage gated sodium channel (VGSC) [22] and the previously demonstrated stimulation of neurite outgrowth by VGSC activators such as PbTx-2 and antillatoxin [26,27], we evaluated the influence of hoiamide A on neurite outgrowth in neocortical neurons
To further explore the molecular mechanisms responsible for hoiamide A-induced neurotoxicity, we evaluated the roles of NMDA receptors, L-type Ca2+ channels, α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors and the Na+-Ca2+ exchanger as targets for hoiamide A-induced neurotoxicity
Summary
Marine cyanobacteria are prolific producers of structurally novel and biologically active natural products and are especially rich in metabolites with toxic properties [1,2,3,4]. Moorea producens (formerly Lyngbya majuscula) is a pantropical marine cyanobacterium, blooms of which have been occurring for decades around the world, in Florida’s Gulf Coastal region of Sanibel Island and the east coast of Queensland, Australia. These blooms of M. producens are reported to have adverse effects on both human populations and domestic animals [5,6], including respiratory irritation, eye inflammation, severe contact dermatitis, gastrointestinal distress as well as fever and headache symptoms [5,7,8,9]. This stereochemically complex metabolite possesses a highly unusual structure that likely derives from a mixed peptide-polyketide biogenetic origin, and includes a peptidic section featuring a ketide-extended and S-adenosyl methionine modified isoleucine moiety, a triheterocyclic fragment bearing two-methylated thiazolines and one thiazole, and a highly oxygenated and methylated
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