Apoptosis induced by domoic acid in mouse cerebellar granule neurons involves activation of p38 and JNK MAP kinases

Abstract

In mouse cerebellar granule neurons (CGN) the marine neurotoxin domoic acid (DomA) induces neuronal cell death, either by apoptosis or by necrosis, depending on its concentration, with apoptotic damage predominating in response to low concentrations (100 nM). DomA-induced apoptosis is due to selective activation of AMPA/kainate receptors, and is mediated by DomA-induced oxidative stress, leading to mitochondrial dysfunction and activation of caspase-3. The p38 MAP kinase and the c-Jun NH 2 -terminal protein kinase (JNK) have been shown to be preferentially activated by oxidative stress. Here we report that DomA increases p38 MAP kinase and JNK phosphorylation, and that this effect is more pronounced in CGNs from Gclm (−/−) mice, which lack the modifier subunit of glutamate-cysteine ligase, have very low glutathione (GSH) levels, and are more sensitive to DomA-induced apoptosis than CGNs from wild-type mice. The increased phosphorylation of JNK and p38 kinase was paralleled by a decreased phosphorylation of Erk 1/2. The AMPA/kainate receptor antagonist NBQX, but not the NMDA receptor antagonist MK-801, prevents DomAinduced activation of p38 and JNK kinases. Several antioxidants (GSH ethyl ester, catalase, phenylbutylnitrone) also prevent DomA-induced phosphorylation of JNK and p38 MAP kinases. Inhibitors of p38 (SB203580) and of JNK (SP600125) antagonize DomA-induced apoptosis. These results indicate the importance of oxidative stress-activated JNK and p38 MAP kinase pathways in DomA-induced apoptosis in CGNs.

Modulatory effects of Terminalia arjuna against domoic acid induced toxicity in Caco-2 cell line

“…Our present results demonstrated that ROS and NO generation were significantly triggered (p \ 0.05) by domoic acid exposure, and the same were decreased by administration of TA in a dose dependent manner. This domoic acid induced oxidative stress was also confirmed by others in in vitro and in vivo studies (Giordano et al 2008;Vranyac-Tramoundanas et al 2011;Pulido 2008). A previous study on California sea lions suggested that oxidative stress may occur during excitotoxicity induced by domoic acid (Giordano et al 2008;Silvagni et al 2005).…”

“…This domoic acid induced oxidative stress was also confirmed by others in in vitro and in vivo studies (Giordano et al 2008;Vranyac-Tramoundanas et al 2011;Pulido 2008). A previous study on California sea lions suggested that oxidative stress may occur during excitotoxicity induced by domoic acid (Giordano et al 2008;Silvagni et al 2005). Lu et al (2013) demonstrated that domoic acid induces inflammatory markers, mitochondrial damage and generates oxidative species, which results in amnesia in domoic acid treated mice through PKC-z-dependent K-ras/Raf/ MEK/ERK1/2 pathway.…”

Modulatory effects of Terminalia arjuna against domoic acid induced toxicity in Caco-2 cell line

“…Our present results demonstrated that ROS and NO generation were significantly triggered (p \ 0.05) by domoic acid exposure, and the same were decreased by administration of TA in a dose dependent manner. This domoic acid induced oxidative stress was also confirmed by others in in vitro and in vivo studies (Giordano et al 2008;Vranyac-Tramoundanas et al 2011;Pulido 2008). A previous study on California sea lions suggested that oxidative stress may occur during excitotoxicity induced by domoic acid (Giordano et al 2008;Silvagni et al 2005).…”

“…This domoic acid induced oxidative stress was also confirmed by others in in vitro and in vivo studies (Giordano et al 2008;Vranyac-Tramoundanas et al 2011;Pulido 2008). A previous study on California sea lions suggested that oxidative stress may occur during excitotoxicity induced by domoic acid (Giordano et al 2008;Silvagni et al 2005). Lu et al (2013) demonstrated that domoic acid induces inflammatory markers, mitochondrial damage and generates oxidative species, which results in amnesia in domoic acid treated mice through PKC-z-dependent K-ras/Raf/ MEK/ERK1/2 pathway.…”

Neurotoxic effects of domoic acid on dopaminergic neurons in primary mesencephalic cell culture

“…Mitochondrial damage seemed to mediate both apoptotic and necrotic cell death of cultured cells. In contrast, apoptotic cell death was reported to occur at the lower concentrations of DomA (< 1 µM) in mouse CGNs [5]. These lower concentrations did not affect both dopaminergic and NeuN+ neurons in our culture model.…”

Muscarinic receptors prevent oxidative stress‐mediated apoptosis induced by domoic acid in mouse cerebellar granule cells

“…Figure 3(b) and (c) shows that in CGNs from Gclm (+/+) mice, activation of caspase‐3 by DomA is completely prevented by carbachol. We had also shown that DomA‐induced apoptosis was mediated by activation of p38 and JNK kinases (Giordano et al. 2008).…”

Modulatory effects of Terminalia arjuna against domoic acid induced toxicity in Caco-2 cell line

“…Our present results demonstrated that ROS and NO generation were significantly triggered (p \ 0.05) by domoic acid exposure, and the same were decreased by administration of TA in a dose dependent manner. This domoic acid induced oxidative stress was also confirmed by others in in vitro and in vivo studies (Giordano et al 2008;Vranyac-Tramoundanas et al 2011;Pulido 2008). A previous study on California sea lions suggested that oxidative stress may occur during excitotoxicity induced by domoic acid (Giordano et al 2008;Silvagni et al 2005).…”

“…This domoic acid induced oxidative stress was also confirmed by others in in vitro and in vivo studies (Giordano et al 2008;Vranyac-Tramoundanas et al 2011;Pulido 2008). A previous study on California sea lions suggested that oxidative stress may occur during excitotoxicity induced by domoic acid (Giordano et al 2008;Silvagni et al 2005). Lu et al (2013) demonstrated that domoic acid induces inflammatory markers, mitochondrial damage and generates oxidative species, which results in amnesia in domoic acid treated mice through PKC-z-dependent K-ras/Raf/ MEK/ERK1/2 pathway.…”

Neurotoxic effects of domoic acid on dopaminergic neurons in primary mesencephalic cell culture

“…Mitochondrial damage seemed to mediate both apoptotic and necrotic cell death of cultured cells. In contrast, apoptotic cell death was reported to occur at the lower concentrations of DomA (< 1 µM) in mouse CGNs [5]. These lower concentrations did not affect both dopaminergic and NeuN+ neurons in our culture model.…”

Muscarinic receptors prevent oxidative stress‐mediated apoptosis induced by domoic acid in mouse cerebellar granule cells

“…Figure 3(b) and (c) shows that in CGNs from Gclm (+/+) mice, activation of caspase‐3 by DomA is completely prevented by carbachol. We had also shown that DomA‐induced apoptosis was mediated by activation of p38 and JNK kinases (Giordano et al. 2008).…”

Modulatory effects of Terminalia arjuna against domoic acid induced toxicity in Caco-2 cell line

“…Our present results demonstrated that ROS and NO generation were significantly triggered (p \ 0.05) by domoic acid exposure, and the same were decreased by administration of TA in a dose dependent manner. This domoic acid induced oxidative stress was also confirmed by others in in vitro and in vivo studies (Giordano et al 2008;Vranyac-Tramoundanas et al 2011;Pulido 2008). A previous study on California sea lions suggested that oxidative stress may occur during excitotoxicity induced by domoic acid (Giordano et al 2008;Silvagni et al 2005).…”

“…This domoic acid induced oxidative stress was also confirmed by others in in vitro and in vivo studies (Giordano et al 2008;Vranyac-Tramoundanas et al 2011;Pulido 2008). A previous study on California sea lions suggested that oxidative stress may occur during excitotoxicity induced by domoic acid (Giordano et al 2008;Silvagni et al 2005). Lu et al (2013) demonstrated that domoic acid induces inflammatory markers, mitochondrial damage and generates oxidative species, which results in amnesia in domoic acid treated mice through PKC-z-dependent K-ras/Raf/ MEK/ERK1/2 pathway.…”

Neurotoxic effects of domoic acid on dopaminergic neurons in primary mesencephalic cell culture

“…Mitochondrial damage seemed to mediate both apoptotic and necrotic cell death of cultured cells. In contrast, apoptotic cell death was reported to occur at the lower concentrations of DomA (< 1 µM) in mouse CGNs [5]. These lower concentrations did not affect both dopaminergic and NeuN+ neurons in our culture model.…”

Muscarinic receptors prevent oxidative stress‐mediated apoptosis induced by domoic acid in mouse cerebellar granule cells

“…Figure 3(b) and (c) shows that in CGNs from Gclm (+/+) mice, activation of caspase‐3 by DomA is completely prevented by carbachol. We had also shown that DomA‐induced apoptosis was mediated by activation of p38 and JNK kinases (Giordano et al. 2008).…”