Abstract
It has been recognized that serotonin 2A receptor (5-HT2A) agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI) impairs serotonergic homeostasis. However, the mechanism of DOI-induced serotonergic behaviors remains to be explored. Moreover, little is known about therapeutic interventions against serotonin syndrome, although evidence suggests that ginseng might possess modulating effects on the serotonin system. As ginsenoside Re (GRe) is well-known as a novel antioxidant in the nervous system, we investigated whether GRe modulates 5-HT2A receptor agonist DOI-induced serotonin impairments. We proposed that protein kinase Cδ (PKCδ) mediates serotonergic impairments. Treatment with GRe or 5-HT2A receptor antagonist MDL11939 significantly attenuated DOI-induced serotonergic behaviors (i.e., overall serotonergic syndrome behaviors, head twitch response, hyperthermia) by inhibiting mitochondrial translocation of PKCδ, reducing mitochondrial glutathione peroxidase activity, mitochondrial dysfunction, and mitochondrial oxidative stress in wild-type mice. These attenuations were in line with those observed upon PKCδ inhibition (i.e., pharmacologic inhibitor rottlerin or PKCδ knockout mice). Furthermore, GRe was not further implicated in attenuation mediated by PKCδ knockout in mice. Our results suggest that PKCδ is a therapeutic target for GRe against serotonergic behaviors induced by DOI.
Highlights
Ginseng (Panax ginseng) is a naturally occurring herb
We investigated the following: (1) whether DOI-mediated 5-HT2A receptor stimulation induces mitochondrial dysfunction and the consequent oxidative burden; (2) whether protein kinase Cδ (PKCδ) activation is involved in DOI-induced serotonergic changes, mitochondrial burden, and serotonergic behaviors using pharmacological and genetic inhibition of PKCδ; (3) whether ginsenoside Re (GRe) affects DOI-induced neuronal and behavioral changes; and (4) whether GRe modulates its effects by affecting PKCδ activation and consequent
Neither GRe nor MDL altered PKCδ knockout (PKCδ KO)-mediated attenuation of DOI-induced deregulation of cytosolic and mitochondrial Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) activities in mice (Figure 6A–D), suggesting that PKCδ is a critical target of antioxidant potential exhibited by GRe or MDL
Summary
Ginseng (Panax ginseng) is a naturally occurring herb. Commercially available ginseng formulations are mainly extracted from the roots of ginseng plants [1]. Effect of GRe or MDL11939 (MDL) on Changes in the Mitochondrial and Cytosolic Activities of Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) Induced by DOI in Wild-Type and PKCδ KO Mice. Neither GRe nor MDL altered PKCδ KO-mediated attenuation of DOI-induced deregulation of cytosolic and mitochondrial SOD and GPx activities in mice (Figure 6A–D), suggesting that PKCδ is a critical target of antioxidant potential exhibited by GRe or MDL. The observations of the present study show that DOI-induced serotonergic behaviors are elicited mainly by mitochondrial oxidative stress, impaired enzymatic antioxidant system (i.e., reduced mitochondrial activity of GPx), mitochondrial translocation of PKCδ, decreases in mitochondrial transmembrane potential and mitochondrial complex (I > II) activity, and increased level of intra-mitochondrial Ca2+; GRe or 5-HT2A receptor antagonist MDL inhibits these morbid scenarios by inhibiting PKCδ. Our results suggest that PKCδ activation followed by mitochondrial burden might contribute to the serotonergic behaviors induced by DOI, and that the GRemediated protective potential regulated by PKCδ inhibition may lead to a novel therapeutic intervention against serotonergic behaviors
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