Effects of Kamikihito on the Noradrenergic System and Its Pharmacokinetic Profile

The presence of treatment-resistant patients underscores the need for novel therapeutic options for affective and anxiety disorders. Kamikihito (KKT), a traditional kampo medicine used to treat mental anxiety and neurosis, has recently attracted attention because of its unique mechanism of action as an oxytocin-activating drug. However, the underlying mechanism remains unclear. In particular, for the optimal use of KKT in clinical practice, clarifying whether KKT affects the monoaminergic system, which is the primary target of first-line antidepressants for these disorders, is essential. By evaluating monoaminergic transporter activity in vitro, we found that KKT inhibited the noradrenaline transporter (NAT). In addition, in the tail suspension test, KKT shortened the duration of immobility posture, indicative of behavioral despair, in lipopolysaccharide-injected mice, similar to desipramine, a NAT inhibitor. Furthermore, a reduction in the immobility time following KKT administration was not observed in mice pretreated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a noradrenergic neurotoxin, indicating that the antidepressant-like effect of KKT is mediated through the noradrenergic system. To identify the ingredients of KKT that are transferred into the blood and brain, we analyzed the blood and brain tissues of mice after KKT administration using mass spectrometry. Geniposide and formononetin were identified and puerarin, gardoside, 3',7-dihydroxy-4'-methoxyisoflavone 7-O-glucoside, and kazonol N were estimated as ingredients that distribute both in the blood and brain. Although these ingredients did not exhibit NAT inhibitory activity, the information presented in this pharmacokinetic study will be a valuable resource for future studies on the molecular mechanisms of KKT action.