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Antidepressant-Like Effect and Mechanism of Action of Honokiol on the Mouse Lipopolysaccharide (LPS) Depression Model

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Antidepressant-Like Effect and Mechanism of Action of Honokiol on the Mouse Lipopolysaccharide (LPS) Depression Model

Bo Zhang et al. Molecules.

Abstract

There is growing evidence that neuroinflammation is closely linked to depression. Honokiol, a biologically active substance extracted from Magnolia officinalis, which is widely used in traditional Chinese medicine, has been shown to exert significant anti-inflammatory effects and improve depression-like behavior caused by inflammation. However, the specific mechanism of action of this activity is still unclear. In this study, the lipopolysaccharide (LPS) mouse model was used to study the effect of honokiol on depression-like behavior induced by LPS in mice and its potential mechanism. A single administration of LPS (1 mg/kg, intraperitoneal injection) increased the immobility time in the forced swimming test (FST) and tail suspension test (TST), without affecting autonomous activity. Pretreatment with honokiol (10 mg/kg, oral administration) for 11 consecutive days significantly improved the immobility time of depressed mice in the FST and TST experiments. Moreover, honokiol ameliorated LPS-induced NF-κB activation in the hippocampus and significantly reduced the levels of the pro-inflammatory cytokines; tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). In addition, honokiol inhibited LPS-induced indoleamine 2,3-dioxygenase (IDO) activation and quinolinic acid (a toxic product) increase and reduced the level of free calcium in brain tissue, thereby inhibiting calcium overload. In summary, our results indicate that the anti-depressant-like effects of honokiol are mediated by its anti-inflammatory effects. Honokiol may inhibit the LPS-induced neuroinflammatory response through the NF-κB signaling pathway, reducing the levels of related pro-inflammatory cytokines, and furthermore, this may affect tryptophan metabolism and increase neuroprotective metabolites.

Keywords: IDO; NF-κB; anti-inflammatory; antidepressant effect; honokiol; tryptophan–kynurenine pathway.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The effects of lipopolysaccharide (LPS) and honokiol on autonomous activity. (A) The distance moved. (B) The velocity of movement. (C) The central region dwelling frequency. (D) The marginal region dwelling frequency. Data are expressed as mean ± SEM (n = 10/group). The results showed no difference between the different groups.
Figure 2
Figure 2
The effects of honokiol on (A) the forced swim test (FST) and (B) the tail suspension test (TST). Data are expressed as mean ± SEM (n = 10/group). ### p < 0.001 LPS vs. control; ** p < 0.01 LPS + Honokiol vs. LPS.
Figure 3
Figure 3
The effects of honokiol on proinflammatory cytokines in serum and in brain tissue. Serum: (A) tumor necrosis factor α (TNF-α), (B) interleukin 1β (IL-1β), and (C) interferon γ (IFN-γ); brain tissue: (D) IFN-γ. Data are expressed as mean ± SEM (n = 9). ### p < 0.001, ## p < 0.01, # p < 0.05 LPS vs. control; *** p < 0.001, ** p < 0.01, * p < 0.05 LPS + Honokiol vs. LPS.
Figure 4
Figure 4
The effects of honokiol on mRNA and protein expression of hippocampal indoleamine 2,3-dioxygenase (IDO) and NF-κB. (A) IDO1 mRNA expression; (B) NF-κB mRNA expression; (C) IDO protein expression; (D) NF-κB protein expression; (E) The western blot bands. Data are expressed as mean ± SEM (n = 8). ### p < 0.001, ## p < 0.01, # p < 0.05 LPS vs. control; *** p < 0.001, ** p < 0.01 LPS + Honokiol vs. LPS.
Figure 5
Figure 5
The effects of honokiol on the metabolites of the tryptophan–kynurenine (TRP–KYN) pathway. (A) serotonin (5-HT); (B) TRP; (C) KYN; (D) kynurenic acid (KYNA); (E) quinolinic acid (QUIN); (F) KYN/TRP ratio; and (G) KYN/KYNA ratio. Data are expressed as mean ± SEM (n = 5). ## p < 0.01, # p < 0.05 LPS vs. control; * p < 0.05 LPS + Honokiol vs. LPS.
Figure 6
Figure 6
The effect of honokiol on free Ca2+ levels in the brain cells of mice. Data are expressed as mean ± SEM (n = 4). ** p < 0.01 LPS + Honokiol vs. LPS.
Figure 7
Figure 7
IDO pathway and tryptophan metabolism pathway. Notes: Tryptophan catabolism through the kynurenine pathway involves IDO as an intracellular rate–limiting enzyme. Pro-inflammatory cytokine is upregulated by LPS regulated by NF-κB. Activation of NF-κB results in the release of pro-inflammatory cytokines, which in turn, activates IDO activity. Tryptophan may be metabolized to serotonin or alternatively, is metabolized via the kynurenine pathway. Tryptophan is metabolized to kynurenine by indoleamine 2,3-dioxygenase. Kynurenine is then converted via kynurenine aminotransferases (KAT) to kynurenic acid, a neuroprotective molecule as it antagonizes glutamate receptor-induced neurotoxicity. In addition, kynurenine can also be converted to 3-hydroxykynurenine by kynurenine-3-monooxygenase (KMO), for which evidence is accumulating of its neurotoxic capability. Sequential conversion to 2-amino-3-carboxymuconate-semialdehyde is the penultimate step leading to enzymatic production of (neuroprotective) picolinic acid, and the (non-enzymatic) production of the well-known neurotoxic compound quinolinic acid. Further conversion of QUIN to the essential cofactor NAD+ is catalysed by quinolinate phosphoribosyltransferase (QPRT).
Figure 8
Figure 8
The structure of honokiol (Chemical formula: C18H18O2; Molecular weight: 266.34).

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