Abstract
BackgroundDomoic acid (DA) is an excitatory amino acid analogue of kainic acid (KA) that acts via activation of glutamate receptors to elicit a rapid and potent excitotoxic response, resulting in neuronal cell death. Recently, DA was shown to elicit reactive oxygen species (ROS) production and induce apoptosis accompanied by activation of p38 mitogen-activated protein kinase (MAPK) in vitro. We have reported that WDR35, a WD-repeat protein, may mediate apoptosis in several animal models. In the present study, we administered DA to rats intraperitoneally, then used liquid chromatography/ion trap tandem mass spectrometry (LC-MS/MS) to identify and quantify DA in the brains of the rats and performed histological examinations of the hippocampus. We further investigated the potential involvement of glutamate receptors, ROS, p38 MAPK, and WDR35 in DA-induced toxicity in vivo.ResultsOur results showed that intraperitoneally administered DA was present in the brain and induced neurodegenerative changes including apoptosis in the CA1 region of the hippocampus. DA also increased the expression of WDR35 mRNA and protein in a dose- and time-dependent manner in the hippocampus. In experiments using glutamate receptor antagonists, the AMPA/KA receptor antagonist NBQX significantly attenuated the DA-induced increase in WDR35 protein expression, but the NMDA receptor antagonist MK-801 did not. In addition, the radical scavenger edaravone significantly attenuated the DA-induced increase in WDR35 protein expression. Furthermore, NBQX and edaravone significantly attenuated the DA-induced increase in p38 MAPK phosphorylation.ConclusionIn summary, our results indicated that DA activated AMPA/KA receptors and induced ROS production and p38 MAPK phosphorylation, resulting in an increase in the expression of WDR35 in vivo.
Highlights
Domoic acid (DA) is an excitatory amino acid analogue of kainic acid (KA) that acts via activation of glutamate receptors to elicit a rapid and potent excitotoxic response, resulting in neuronal cell death
Examination of the relationships between amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/KA receptors, reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (MAPK) As Harper et al [10] reported that ROS activates the p38 MAPK pathway, we investigated whether intraperitoneal DA administration increases p38 MAPK phosphorylation in the rat hippocampus
No significant change in the expression of p38 MAPK protein was observed. These results suggested that activation of the AMPA/KA receptor resulting in ROS generation followed by p38 MAPK phosphorylation might be involved in the DAinduced upregulation of WD repeat-containing protein 35 (WDR35)
Summary
Domoic acid (DA) is an excitatory amino acid analogue of kainic acid (KA) that acts via activation of glutamate receptors to elicit a rapid and potent excitotoxic response, resulting in neuronal cell death. DA was shown to elicit reactive oxygen species (ROS) production and induce apoptosis accompanied by activation of p38 mitogen-activated protein kinase (MAPK) in vitro. A recent study demonstrated that DA-induced cell death in primary neuronal cultures involves activation of p38 MAPK, and antioxidants prevented p38 MAPK phosphorylation [11]. These lines of evidence suggest that DA induces ROS generation followed by p38 MAPK phosphorylation in vitro. A recent study demonstrated that abnormal ROS levels in the hippocampus of DA-treated mice activate the stressactivated protein kinase/c-Jun amino-terminal kinase (SAPK/JNK) pathway in vivo [14], but no studies have investigated ROS-mediated p38 MAPK signal transduction pathways in the hippocampus after administration of DA
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
