Antidepressant mechanism of catalpol: Involvement of the PI3K/Akt/Nrf2/HO-1 signaling pathway in rat hippocampus

• Published in: European journal of pharmacology 2021-10, Vol.909, p.174396-174396, Article 174396
• Main Authors: Wang, Junming, Chen, Rongxing, Liu, Chen, Wu, Xiaohui, Zhang, Yueyue
• Format: Article
• Language: English
• Subjects: Animals; Antidepressant mechanism; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Antioxidant defense; Depression - diagnosis; Depression - drug therapy; Depression - etiology; Depression - pathology; Depressive behaviors; Disease Models, Animal; Drug Evaluation, Preclinical; Drugs, Chinese Herbal - pharmacology; Drugs, Chinese Herbal - therapeutic use; Heme Oxygenase (Decyclizing) - metabolism; Hippocampus - drug effects; Hippocampus - pathology; Humans; Iridoid Glucosides - pharmacology; Iridoid Glucosides - therapeutic use; Lipid Peroxidation - drug effects; Male; Neurotrophic; NF-E2-Related Factor 2 - metabolism; Oxidative Stress - drug effects; Phosphatidylinositol 3-Kinase - metabolism; PI3K/Akt/Nrf2/HO-1 signaling pathway; Proto-Oncogene Proteins c-akt - metabolism; Rats; Signal Transduction - drug effects; Stress, Psychological - complications
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2021.174396

Catalpol is a major compound in Rehmanniae Radix with outstanding medicinal and nutritional values. Our previous studies have demonstrated catalpol's antidepressant effect, but its mechanisms remain unclear. This study aimed to explore the antidepressant mechanisms of catalpol via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1) pathway. Results demonstrated that chronic unpredictable mild stress (CUMS) for 5 consecutive weeks caused significant decreases in the sucrose preference and the horizontal and vertical scores of open-field test, as well as a significant increase in the swimming-immobility time of rats; catalpol administration significantly reversed the abnormality of these indicators. Further real-time fluorescent quantitative polymerase chain reaction and Western blotting results together showed that CUMS significantly downregulated the expression levels of hippocampal genes and proteins, including PI3K, Akt, Nrf2, HO-1, tropomyosin-related kinase B (TrkB), and brain-derived neurotrophic factor; catalpol administration significantly reversed the abnormal expression of these genes and proteins. CUMS also caused a significant decrease in the hippocampal superoxide dismutase, catalase, glutathione peroxidase, glutathione-s transferase, and reduced glutathione levels, as well as a significant increase in thiobarbituric acid reactive substances level in rats; catalpol administration significantly reversed the abnormality of these indicators. Taken together, this study confirmed for the first time that the antidepressant effect of catalpol on CUMS-induced depression involved the upregulation of the PI3K/Akt/Nrf2/HO-1 signaling pathway, thereby improving the hippocampal neurotrophic, neuroprotective, and antioxidant levels. The PI3K/Akt/Nrf2/HO-1 pathway-related molecules may serve as potential new biomarkers and candidate molecular targets for catalpol's antidepressant effects. [Display omitted] •Catalpol exerted a clear antidepressant effect on CUMS-induced depressive rats.•Catalpol upregulated PI3K/Akt/Nrf2/HO-1 proteins in CUMS-exposed rat hippocampus.•Catalpol upregulated PI3K/Akt/Nrf2/HO-1 genes levels in CUMS-exposed rat hippocampus.•Catalpol enhanced BDNF/TrkB proteins and genes expression levels in rat hippocampus.•Catalpol enhanced antioxidant defense and neurotrophic protection in rat hippocampus.