Dihydromyricetin ameliorates social isolation-induced anxiety by modulating mitochondrial function, antioxidant enzymes, and BDNF

Alzahra J Al Omran; Saki Watanabe; Ethan C Hong; Samantha G Skinner; Mindy Zhang; Jifeng Zhang; Xuesi M Shao; Jing Liang

doi:10.1016/j.ynstr.2022.100499

Dihydromyricetin ameliorates social isolation-induced anxiety by modulating mitochondrial function, antioxidant enzymes, and BDNF

Neurobiol Stress. 2022 Oct 30:21:100499. doi: 10.1016/j.ynstr.2022.100499. eCollection 2022 Nov.

Authors

Alzahra J Al Omran¹, Saki Watanabe¹, Ethan C Hong¹, Samantha G Skinner¹, Mindy Zhang¹, Jifeng Zhang¹, Xuesi M Shao², Jing Liang¹

Affiliations

¹ Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA, 90033, USA.
² Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.

Abstract

Stress has been implicated in the etiology of neurological and psychological illnesses. Chronic social isolation (SI) is a psychological stressor that provokes neurobehavioral changes associated with psychiatric disorders, including anxiety disorders. Mitochondria dysfunction and oxidative stress are hallmarks of anxiety pathogenesis. Here we demonstrate the effects of SI-induced stress on mitochondrial function, antioxidative enzymes, autophagy, and brain derivative neurotrophic factor (BDNF). SI induced a reduction in electron transport chain subunits C-I, C-II, and C-VI and an increase in hydrogen peroxide. Treatment with dihydromyricetin (DHM), extracted from Ampelopsis grossedentata, counteracted these changes. A dramatic increase in several primary mitochondrial antioxidative enzymes such as superoxide dismutase 2 (SOD2), heme oxygenase-1 (HO-1), peroxiredoxin-3 (PRDX3), and glutathione peroxidase 4 (GPX4) was observed after SI and a repeated episode of SI. Both SI and repeated SI induced a reduction in sequestosome 1 (SQSTM1/p62). However, only repeated SI modulated autophagy primary protein beclin-1 (Bcl-1). In addition, SI and repeated SI modulated the BDNF-TrkB signaling pathway and the phosphorylation of the downstream extracellular signal-regulated MAP kinase1/2 (p-Erk p42 and p-Erk p44) cascade. DHM treatment ameliorated these changes. Collectively, we demonstrated that DHM treatment counteracted the effects of SI and repeated SI on antioxidative enzymes, autophagy, and the BDNF-TrkB signaling pathway. These findings highlight the molecular mechanisms that partially explain the anxiolytic effects of DHM.

Keywords: Antioxidative enzymes; Anxiety; Autophagy; BDNF; BDNF-TrkB; Dihydromyricetin (DHM); Mitochondria; Oxidative stress; Repeated social isolation; Social isolation; Stress.