title: Involvement of JNK and caspase activation in hoiamide A-induced neurotoxicity in neocortical neurons.
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.
authors: 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. zycao1999@hotmail.com.|Department of Pharmacology, School of Medicine, Creighton University, Omaha, NE 68178, USA. zycao1999@hotmail.com.
authors: Zhengyu
authors: Z
authors: Cao
authors: 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. Xichun_li@163.com.
authors: Xichun
authors: X
authors: Li
authors: 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. imzouxiaohan@163.com.
authors: Xiaohan
authors: X
authors: Zou
authors: Department of Pharmacology, School of Medicine, Creighton University, Omaha, NE 68178, USA. michael.greenwood@unmc.edu.
authors: Michael
authors: M
authors: Greenwood
authors: 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. wgerwick@ucsd.edu.
authors: William H
authors: WH
authors: Gerwick
authors: Department of Pharmacology, School of Medicine, Creighton University, Omaha, NE 68178, USA. tfmurray@creighton.edu.
authors: Thomas F
authors: TF
authors: Murray
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D000458:Cyanobacteria / Q000737:chemistry; D047630:Depsipeptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005068:Eutrophication; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009336:Necrosis; D019579:Neocortex / Q000166:cytology* / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology*; D020258:Neurotoxicity Syndromes / Q000201:enzymology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D047428:Protein Kinase Inhibitors; C545734:hoiamide A; D048670:MAP Kinase Kinase 4; D020169:Caspases