Antidepressant Mechanism of Kaixinsan and Its Active Compounds Based on Upregulation of Antioxidant Thioredoxin

Abstract

Objectives. Kaixinsan (KXS), a traditional Chinese medicine formula, has been demonstrated to be effective in the treatment of depression. The present study applied a network pharmacology approach to dig out the new targets and mechanism of action of KXS and the active compounds in the treatment of depression. Methods. A network pharmacology approach based on public databases including ADME (absorption, distribution, metabolism, and excretion) evaluation, targets prediction, construction of networks, and molecule docking was used and validated the predicted new antioxidant targets and mechanisms in vitro. Based on an in vitro experiment, we verified the AKT1/Nrf2 pathway related to the thioredoxin (Trx) antioxidant mechanism. Results. The present study sorted 31 pharmacologically active components (kaempferol, ginsenoside rh2, ginsenoside rh4, stigmasterol, etc.) through the ADME algorithm from KXS. 136 potential molecular targets (AKT1, TNF, IL-1b, JUN, ESR1, NOS3, etc.) were predicted, of which there were 69 targets clearly related to depression. By compound-depression targets (C-DTs) network constructed, and protein-protein interaction networks (PPI) and KEGG pathway enrichment analyzed, we identified active compounds mediating depression-related targets to exert synergism on the predictive AKT1/Nrf2 pathway related to thioredoxin (Trx) antioxidant mechanism and other inflammation-related signaling pathways as well as neurotransmitter related signaling pathways. In the H2O2 induced SH-SY5Y cell damage model, this showed kaempferol and ginsenoside rh2 could enhance the activity of the Trx system by upregulation of AKT1 to activate Nrf2 in vitro. Conclusions. Taken together, by comprehensive systems pharmacology approach analysis, we found that KXS and its active compounds might exhibit antioxidant effects by stimulating the AKT1/Nrf2 pathway in the treatment of depression, which might shed new light on innovative therapeutic tactics for the new aspects for depression in traditional Chinese medicine in future studies.

Research on the quality markers of antioxidant activity of Kai-Xin-San based on the spectrum–effect relationship

“…In this study, even though all of the KXS contained α-asarone, its content varied from batch to batch. As a result, the SC 50 values of 12 batches of KXS were in the range of 3.69–37.32 μg/mL, indicating that KXS had a strong free radical scavenging ability with concentration dependence, and the antioxidant activity of KXS was correlated with the content of metabolites ( Lee et al, 2016 ; Li et al, 2022 ). Meanwhile, these results objectively reflect the necessity of establishing a stable quality control system for scientific development of TCM.…”

Role of Natural Compounds Modulating Heme Catabolic Pathway in Gut, Liver, Cardiovascular, and Brain Diseases

“…AKT2/NRF2 pathways Kaempferol Ginsenoside rh2 [71] Upregulation of the antioxidant enzyme thioredoxin linked to antidepressant mechanism.…”

“…The antioxidant properties of curcumin have also been shown in neurons, by a NRF2/PKCδ-mediated induction of p62 (ubiquitin sensor and selective autophagy receptor) phosphorylation [70]. Although the in vitro neuroprotective action of curcumin (and astragaloside) in depression has been suggested to be mediated by the tyrosine protein kinase (TRK) β/MAPK/PI3K/CREB signaling pathways-induced upregulation of BDNF (brain-derived neurotrophic factor) [177], in in vivo models, the antidepressant properties of curcumin have been found to be involved via AKT1, NRF2, and ARE signaling [65,71]. Furthermore, in vivo, dietary supplementation with curcumin has been shown to reverse the microglial and astrocytes activation via NRF2/TLR4/NFkB/RAGE (receptor for advance glycation end products) signaling in a rodent model ethanol-induced neurotoxicity [68], and acts as an antioxidant in intracerebral hemorrhage, traumatic brain injury, quinoline acid-induced glutamate neurotoxicity, and ischemic injury models via the NRF2/HMOX1/AKT pathways [49,62,63,66,67,72].…”

“…Kaempferol and ginsenoside rh2, the most active principle of the Kaixinsan formula, used as an antidepressant in traditional Chinese medicine, are effective in reverting the pro-oxidant cellular status of SH-SY5Y cells exposed to H 2 O 2 by increasing thioredoxin reductase activity via NRF2/AKT [71].…”