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Mar. Drugs 2015, 13(2), 903-919;

Involvement of JNK and Caspase Activation in Hoiamide A-Induced Neurotoxicity in Neocortical Neurons

State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of TCM, China Pharmaceutical University, Nanjing 211198, China
Department of Pharmacology, School of Medicine, Creighton University, Omaha, NE 68178, USA
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA
Authors to whom correspondence should be addressed.
Academic Editor: Vítor Vasconcelos
Received: 31 December 2014 / Revised: 24 January 2015 / Accepted: 3 February 2015 / Published: 10 February 2015
(This article belongs to the Special Issue Emerging Marine Toxins)
PDF [1071 KB, uploaded 24 February 2015]


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. View Full-Text
Keywords: apoptosis; caspase; c-Jun N-terminal kinase; hoiamide A; necrosis apoptosis; caspase; c-Jun N-terminal kinase; hoiamide A; necrosis

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Cao, Z.; Li, X.; Zou, X.; Greenwood, M.; Gerwick, W.H.; Murray, T.F. Involvement of JNK and Caspase Activation in Hoiamide A-Induced Neurotoxicity in Neocortical Neurons. Mar. Drugs 2015, 13, 903-919.

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