Kamikihito Ameliorates Lipopolysaccharide-Induced Sickness Behavior <i>via</i> Attenuating Neural Activation, but Not Inflammation, in the Hypothalamic Paraventricular Nucleus and Central Nucleus of the Amygdala in Mice

Abstract

Sickness behavior is a series of behavioral and psychological changes that develop in those stricken with cancers and inflammatory diseases. The etiological mechanism of sickness behavior is not known in detail, and consequently there are no established standard therapies. Kamikihito (KKT), a Kampo (traditional Japanese herbal) medicine composed of 14 herbs, has been used clinically to treat psychiatric dysfunction. Previously, we found that KKT ameliorated sickness behavior in mice inoculated with murine colon 26 adenocarcinoma cells. In this study, we examined the effects of KKT on bacterial endotoxin lipopolysaccharide (LPS)-induced sickness behavior in mice. The administration of LPS caused the emotional aspects of sickness behavior, such as loss of object exploration, social interaction deficit, and depressive-like behavior. LPS also induced mRNA expression for cyclooxygenase (COX)-2, interleukin (IL)-1β and IL-6, and increased the number of c-Fos immunopositive cells in the hypothalamus and amygdala. KKT ameliorated the behavioral changes and reversed the increases in c-Fos immunopositive cells in the two brain regions, but did not influence the mRNA expression. These results suggest that KKT ameliorates sickness behavior via the suppression of neural activation without anti-inflammatory effects, and that KKT has the potential to treat sickness behavior.Key words Kamikihito; sickness behavior; lipopolysaccharide; hypothalamus; amygdala Sickness behavior refers to a set of adaptive behavioral and psychological changes, such as fatigue, anhedonia, depression, anxiety, apathy and loss of appetite, that occur in patients with cancer or infections.1-3) Several studies have shown that activation of the immune system based on increases in release of inflammatory cytokines is associated with sickness behavior, 2,4-13) but the etiological mechanism is not known in detail. Thus, there are no standard therapies for sickness behavior.The mechanism of induction of sickness behavior by immune system activation has been examined in bacterial endotoxin lipopolysaccharide (LPS)-treated animal models. Administration of LPS induces neuroinflammation and neural activation in rodent brain, and causes sickness behavior. 11,14) Neural activation in the paraventricular nucleus (PVN) of the hypothalamus and the central nucleus of the amygdala (CeA) and emotional aspects of behavioral changes such as depressive-like behavior, social behavior deficits and loss of interest continue for more than 24 h after LPS administration. 14,15) These studies suggest that neural activation of the PVN and CeA is involved in LPS-induced sickness behavior.Kamikihito (KKT) is a Kampo (Japanese herbal) medicine is used clinically to treat psychiatric dysfunctions such as anxiety, insomnia, amnesia and depression. Pharmacological studies have shown that KKT is effective for behavioral abnormalities and cognitive dysfunction induced by beta-amyloid, methyl-beta-carboline-3-carboxylate, scopolamine, delta-9-tetrahydrocannabinol, ovariectomy, and senescen...

Sickness and the Social Brain: How the Immune System Regulates Behavior across Species

“…Following exposure to endotoxin (LPS), IL-6 and tumor necrosis factor α (TNFα) levels positively correlate with fMRI activation in the amygdala [Inagaki et al, 2012] and ventral striatum [Inagaki et al, 2015] in humans. In mice, it has been shown by multiple groups that LPS robustly increases pro-inflammatory cytokine production and neural activation in the hypothalamus, while decreasing dopamine [Frenois et al, 2007;Araki et al, 2016;Burfeind et al, 2016Burfeind et al, , 2018Zenz et al, 2019;Veit et al, 2021]. Additionally, administration of LPS causes upregulation of the pro-inflammatory cytokines interleukin-1β (IL-1β), TNFα, and IL-6 in the PFC [Audet et al, 2011] and causes degradation of dopamine and serotonin in the nucleus accumbens [Dölen et al, 2013;van Heesch et al, 2014;Korte-Bouws et al, 2018].…”

Kamikihito Enhances Cognitive Functions and Reward-Related Behaviors of Aged C57BL/6J Mice in an Automated Behavioral Assay System

“…Although clinical evidence of the efficacy of KKT to treat neuroses, anxiety, or other psychogenic problems remains inadequate, recent small-scale research has revealed that it is effective for depression, anxiety, and fatigue in cancer patients (Tamada et al, 2018), and for menopausal symptoms including insomnia in patients after gynecological tumor treatment (Yoshimura et al, 2018). Similar psychotropic-like effects have been demonstrated in animal experiments; KKT suppressed depression-like behavior in lipopolysaccharidetreated mice (Araki et al, 2016), and reversed anxiety-like behaviors in mice and rats induced by an inverse agonist of GABA A receptors (Nishizawa and Yamashita, 1997). Anxiolytic effects of repeated KKT treatment were observed in non-stressed wild-type mice (Kuribara and Maruyama, 1996).…”

Traditional Chinese medicine Jia Wei Gui Pi Tang improves behavioural and psychological symptoms of dementia and favourable positive emotions in patients

“…Restoration of degenerated axons and synapses may be associated with memory facilitation by this TCM 22 . Araki et al 23 . reported that Jia Wei Gui Pi Tang ameliorated sickness behaviour in mice inoculated with murine colon 26 adenocarcinoma cells.…”

“…Restoration of degenerated axons and synapses may be associated with memory facilitation by this TCM. 22 Araki et al 23 reported that Jia Wei Gui Pi Tang ameliorated sickness behaviour in mice inoculated with murine colon 26 adenocarcinoma cells. Furthermore, Adachi et al 24 reported that this TCM reduced depressivelike behaviours and hippocampus neurogenesis in chronic restraint stressed rats.…”