Involvement of JNK and caspase activation in hoiamide A-induced neurotoxicity in neocortical neurons

Zhengyu Cao, Xichun Li, Xiaohan Zou, Michael Greenwood, William H. Gerwick, Thomas F. Murray

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)903-919
Number of pages17
JournalMarine Drugs
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2015

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Caspases
Neurons
Cyanobacteria
Caspase 3
Lactic Acid
Oxidoreductases
Depsipeptides
hoiamide A
Caspase Inhibitors
MAP Kinase Signaling System
Inhibitory Concentration 50
Cell Death
Necrosis
Phosphorylation
Apoptosis
Health

All Science Journal Classification (ASJC) codes

  • Drug Discovery

Cite this

Involvement of JNK and caspase activation in hoiamide A-induced neurotoxicity in neocortical neurons. / Cao, Zhengyu; Li, Xichun; Zou, Xiaohan; Greenwood, Michael; Gerwick, William H.; Murray, Thomas F.

In: Marine Drugs, Vol. 13, No. 2, 01.02.2015, p. 903-919.

Research output: Contribution to journalArticle

Cao, Zhengyu ; Li, Xichun ; Zou, Xiaohan ; Greenwood, Michael ; Gerwick, William H. ; Murray, Thomas F. / Involvement of JNK and caspase activation in hoiamide A-induced neurotoxicity in neocortical neurons. In: Marine Drugs. 2015 ; Vol. 13, No. 2. pp. 903-919.
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