Kai-Xin-San ameliorates fluoxetine-resistant depressive-like behaviors by modulating tryptophan-kynurenine metabolic homeostasis in a rodent model.

ETHNOPHARMACOLOGICAL RELEVANCE: Kai-Xin-San (KXS) has been used for centuries in the treatment of depression. However, its antidepressant efficacy and the mechanisms involved in treatment-resistant depression (TRD) are not well understood.

AIM OF THE STUDY: This study aimed to examine whether KXS can improve TRD by restoring tryptophan (TRP) metabolism balance.

MATERIALS AND

METHODS

Fluoxetine-resistant depression (FRD) rats were identified through chronic unpredictable mild stress (CUMS) and subsequently treated with fluoxetine (10 mg/kg/d, ip.). Following this, KXS (491 mg/kg/d, po.) was administered to the FRD rats for a duration of two weeks. The impacts of KXS on depressive-like behaviors, TRP metabolism, blood-brain barrier (BBB) integrity, and the proliferations of neurons, microglia and astrocytes were examined in FRD rats. Lipopolysaccharide (LPS)-treated BV2 conditioned medium (CM) was used to investigate the neuroprotective effects of KXS through the inhibition of the kynurenine pathway (KP) in microglia. Molecular docking was applied to clarify the interactions between the active compounds in KXS and key enzyme in KP.

RESULTS

In vivo, KXS improved depression-like behaviors in FRD rats, restoring TRP metabolism in both periphery and hippocampus by reducing indoleamine-2,3-dioxygenase (IDO 1), tryptophan-2,3-dioxygenase (TDO 2) and kynurenine-3-monooxygenase (KMO). This was evidenced by elevated levels of kynurenine (KYN), kynurenic acid (KYNA), KYN/TRP and KYNA/quinolinic acid (QA), alongside diminished concentrations of QA and 5-HT in serum, as well as increased KYNA, 5-HT and KYNA/QA, and decreased levels of KYN, QA and KYN/TRP in hippocampus. KXS attenuated neuroinflammation, alleviated BBB impairment by elevating Claudin 5 expressions, promoted neurogenesis, and inhibited microglial proliferation in hippocampus. The in vitro results further confirmed the advantageous effects of KXS on neurons through the inhibition of IDO 1 in microglia, as evidenced by increased viability, postsynaptic density protein 95 (PSD 95), brain-derived neurotrophic factor (BDNF) and neurofilament proteins (NF 68/160/200) in BV2 CM-treated SH-SY5Y cells. Moreover, molecular docking indicated that ginsenoside Rg3 may be the principal bioactive compound in KXS.

CONCLUSION

KXS may partially alleviate FRD by influencing TRP metabolism and related BBB integrity, neurogenesis and microglial proliferation, with these effects mainly attributed to ginsenoside Rg3.