Mahonia Alkaloids (MA) Ameliorate Depression Induced Gap Junction Dysfunction by miR-205/Cx43 Axis

Abstract

Depression has become an important disease threatening human health. In recent years, the e cacy of Traditional Chinese Medicine (TCM) in treating the disease has become increasingly prominent, so it is meaningful to nd new antidepressant TCM. Mahonia fortune (Lindl.) Fedde is a primary drug in traditional formulas for the treatment of depression, however, the exact mechanism of its action is unclear. This study aimed to research the effect of MA on the improvement of gap junction function in depression via the miR-205/Cx43 pathway. The antidepressant effects of MA were observed by a rat model of reserpine-induced depression and a model of corticosterone (CORT)-induced astrocytes. The concentrations of neurotransmitters were measured by ELISA, the expression of Connexin 43 (Cx43) protein was measured by Immunohistochemistry, the expression of Cx43, BDNF, CREB proteins were measured by western-blot, the pathological changes of prefrontal cortex were observed by hematoxylineosin (H&E) staining. The binding of miR-205 and Cx43 was veri ed with a Luciferase reporter gene. Gap junction dysfunction detected by uorescent yellow staining. The results con rmed that MA remarkably decreased miR-205 expression and increased Cx43, BDNF, CREB expression in depression rat and CORTinduced astrocytes. In addition, after overexpression of miR-205 in vitro, MA signi cantly increased Cx43, BDNF and CREB expression in CORT-induced astrocytes. Thus, MA may target Cx43 through miR-205 to regulate CREB/BDNF signaling pathway to improve depressive behavior. Highlights Mahonia alkaloids (MA) ameliorate depression-like behavior of rats. MA ameliorate depression-like behavior by down-regulating miR-205 expression. GJA1 (Cx43) is a target gene of miR-205. MA regulate Cx43 protein. MA activate CREB/BDNF pathway to improve depression-like behavior through miR-205/Cx43.

Active Fraction of Polyrhachis Vicina Roger (AFPR) Ameliorate Depression Induced Inflammation Response by FTO/miR-221-3p/SOCS1 Axis

“…Motion inhibition test (MIT) was as described previously. 33 , 34 In short, the animal was placed in the center of a circular whiteboard 40 cm in diameter and observed for 30s, and the time the animal left the circular whiteboard was recorded. The experiment simulated a state of reduced movement in depressed animals.…”

Exploring Astrocyte-Mediated Mechanisms in Sleep Disorders and Comorbidity

“…Studies have demonstrated that inhibition of connexin 43 exacerbates depressionlike behavior [180]. Supporting these findings, further research has indicated that the gap junction channels of astrocytes could potentially serve as targets for new antidepressant drug development [181,182]. Approaches such as enhancing astrocytic lactate production or promoting lactate uptake by neurons could potentially restore energy balance, improve sleep quality, and ameliorate comorbid conditions.…”

Perspective and Therapeutic Potential of the Noncoding RNA–Connexin Axis

“…In a study using an unpredictable chronic mild stress (UCMS)-induced mouse model of depression, miR-221/222 directly bound to the 3′ untranslated regions (3′ UTR) of Cx43 mRNA and downregulated Cx43 protein levels; this could be reversed by genistein treatment, subsequently ameliorating depression-like behaviors in the mice [ 21 ]. miR-205 also targeted the Gja1 gene, which encodes the Cx43 protein [ 22 ]. The administration of Mahonia alkaloids reduced miR-205 content and consequently improved Cx43 levels, alleviating depression in reserpine-treated rats [ 22 ].…”

“…miR-205 also targeted the Gja1 gene, which encodes the Cx43 protein [ 22 ]. The administration of Mahonia alkaloids reduced miR-205 content and consequently improved Cx43 levels, alleviating depression in reserpine-treated rats [ 22 ]. miR-106a was confirmed to bind to the 3′ UTR of Cx43 mRNA, and an miR-106a antagonist could repress apoptosis, alleviate oxidative stress, and enhance Cx43 protein content in glucose oxidase-treated rat cochlear marginal cells [ 23 ].…”

“…Cx43 plays a key role in neuroinflammation [ 108 , 109 ]. Antagomirs to miR-221/222 [ 21 ], miR-205 [ 22 ], and miR-224 [ 27 ] can upregulate Cx43 protein levels in glial cells and have anti-neuroinflammatory potential. Carefully designed siRNAs and antisense oligonucleotides can suppress upstream ncRNAs, such as lncRNA ANRIL [ 61 ] to rescue Cx43 or to reduce Cx43 levels by suppressing lncRNA CCRR [ 44 ] and lncRNA MALAT1 [ 62 ].…”