Regulation of the kynurenine/serotonin pathway by berberine and the underlying effect in the hippocampus of the chronic unpredictable mild stress mice

Jan 20, 2022Behavioural brain research

Berberine's influence on the balance between kynurenine and serotonin in the memory area of mice under chronic mild stress

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Abstract

A 21-day chronic unpredictable mild stress model established in mice demonstrated significant alterations in the kynurenine/serotonin pathway associated with depression.

Depressive-like behavior was indicated by decreased locomotor activity, increased immobility time, reduced body weight, and lower sucrose preference in the model group.
Compared to the normal group, the control group exhibited a significant increase in the ratio of kynurenine to tryptophan and a decrease in the ratio of serotonin to 5-hydroxyindoleacetic acid.
Fluoxetine and berberine treatment improved the disrupted ratios of kynurenine/tryptophan and serotonin/5-hydroxyindoleacetic acid.
The mRNA levels of indoleamine 2,3-dioxygenase 1 (IDO1) and monoamine oxidase A (MAOA) were significantly upregulated in the control group but downregulated following fluoxetine and berberine treatment.
Berberine treatment was associated with downregulation of IDO1 and MAOA and upregulation of dopamine decarboxylase (DDC) in the hippocampus.

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BACKGROUND: Depression is a common mental disorder and is one of the main causes of disability. Berberine (BBR), the major constituent alkaloid originally from the famous Chinese herb Huanglian (Coptis chinensis), has been shown to exert antidepressant-like effects. This study was to investigate the hypothesis that BBR treats depressive-like behavior by shifting the balance of the kynurenine (KYN)/serotonin (5-HT) pathway toward the 5-HT pathway through downregulated indoleamine 2,3-dioxygenase 1 (IDO1), monoamine oxidase A (MAOA) and upregulated dopamine decarboxylase (DDC) in hippocampus.

METHOD: A chronic unpredictable mild stress (CUMS) mice model of depression was established via 21 days unpredictable stimulation. Then the mice were randomly assigned into six groups, namely control, model, fluoxetine [FLU, (10 mg/kg)], BBRL (25 mg/kg), BBRM (50 mg/kg), and BBRH (100 mg/kg) groups. Behavioral assessments were conducted to evaluate the antidepressant effects of BBR. The levels of 5-HT, KYN, tryptophan (TRP), and 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus were estimated using high performance liquid chromatography (HPLC). The mRNA and protein levels of DDC, MAOA and IDO1 in hippocampus were detected by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot (WB), respectively.

RESULT: The results showed that a successful CUMS mice model was established through 21 days of continuous unpredictable stimulation, as indicated by the significant decrease in locomotor activity and increase in immobility time, reduction in body weight and sucrose preference rate etc. Compared with the normal group, the concentrations of KYN/TRP had significantly increased (p<0.01) and 5-HT/5-HIAA had decreased (p<0.05) at day 21 in the control group, but then improved after drug treatment with FLU and BBR. Compared with the normal group, the mRNA of IDO1 and MAOA were significantly upregulated (p<0.05) in the control group, MAOA and IDO1 gene were downregulated by FLU and BBR treatment. Protein expressions of IDO1 and MAOA was significantly increased (p<0.05) and DDC downregulated (p<0.01). BBR treatment downregulated IDO1 and MAOA, upregulated DDC. ## # # # ##

CONCLUSIONS: BBR reversed the abnormalities of the KYN/5-HT pathway in depressed mice and achieved an excellent antidepressant effect. Its direct impact may be observed as changes in biological indicators in mice hippocampus tissue.

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Regulation of the kynurenine/serotonin pathway by berberine and the underlying effect in the hippocampus of the chronic unpredictable mild stress mice

Abstract

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