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A Chronic Immobilization Stress Protocol for Inducing Depression-Like Behavior in Mice
Published on: May 15, 2019
San Wei Tan Xiang (SWTX) ameliorates depressive-like behaviors by modulating 6-phosphogluconate dehydrogenase (6PGD)
Yuyan Ling1, Ling Gu2, Shuxun Feng1
1School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
Ethnopharmacological Relevance:
San Wei Tan Xiang (SWTX), known as Zandansong Tang in Tibetan medicine, is recorded in the Four Medical Classics and is commonly used in Tibetan medicine. Recently, it has been found to exhibit good therapeutic efficacy in patients with depression.
Aim Of The Study:
This study aims to assess the therapeutic benefits of SWTX for depression and to elucidate the underlying mechanism whereby SWTX improves depressive-like behavior via regulation of 6-phosphogluconate dehydrogenase (6PGD).
Materials And Methods:
A depression model was established via corticosterone (CORT) stimulation, followed by treatment with San Wei Tan Xiang (SWTX). Behavioral tests were conducted to evaluate emotional changes, while Nissl staining and ELISA were employed to assess histopathological alterations and biochemical indices, respectively. 6PGD activity was measured using commercial enzyme activity assay kits. Protein expression levels were analyzed by immunofluorescence and western blotting. Furthermore, oxidative stress status in mouse brain was evaluated through malondialdehyde, superoxide dismutase, and glutathione assays, along with ROS levels using flow cytometry.
Results:
SWTX exhibited significant antidepressant activity in a mouse model of depressive-like behavior by activating 6PGD to restore cerebral redox homeostasis. This activation enhanced pentose phosphate pathway (PPP) metabolism and NADPH generation, consequently ameliorating mitochondrial function and attenuating mitophagy. In addition, the potential active ingredient in SWTX, naringenin, is associated with increasing 6PGD activity and promoting NADPH biosynthesis, thereby restoring redox homeostasis, maintaining mitochondrial integrity, and thus weakening the compensatory upregulation of mitochondria mediated by PINK1/Parkin. Through molecular docking and Bio-Layer Interferometry (BLI) assays, we identified naringenin as a potential bioactive component in the therapeutic effects of SWTX. Naringenin also demonstrated beneficial effects in investigating mitochondrial damage caused by oxidative stress due to 6PGD downregulation and excessive activation of PINK1/PARK2/Parkin. Therefore, naringenin may be one of the active components responsible for the antidepressant effects of SWTX.
Conclusions:
SWTX ameliorates depressive-like behaviors by coordinating 6PGD activity and mitochondrial function, including restoring NADPH generation via the PPP to alleviate oxidative stress, and improving mitochondrial quality through the PARK2/Parkin/PINK1 pathway. These findings highlight SWTX as a promising holistic therapeutic approach for depression, reflecting the multi-component and multi-target pharmacological characteristics of traditional formulations. Further exploratory analysis suggested that naringenin, one of the SWTX-derived absorbable constituents, may contribute to 6PGD/NADPH pathway regulation and neuronal protection in CORT-treated primary hippocampal neurons. However, the naringenin-related results should be interpreted cautiously because additional pharmacokinetic, dose-response, and direct structural validation studies are required.
