Ginsenoside Rg1 Ameliorates Neuroinflammation via Suppression of Connexin43 Ubiquitination to Attenuate Depression

Abstract

Depression is an inflammation-associated disease that results in major depression as inflammation increases and progresses. Ginsenoside Rg1 (Rg1), the major bioactive ingredient derived from ginseng, possesses remarkable anti-depressant and anti-inflammatory effects. Our previous studies showed that the pathogenesis of depression was concomitant with the acceleration of connexin43 (Cx43) ubiquitin degradation, while Rg1 could upregulate Cx43 expression to attenuate depression. However, whether the ubiquitination of Cx43 is the specific correlation between depression and inflammation, and how Rg1 ameliorates neuroinflammation to attenuate depression, are still under investigation. In in vivo experiments, Rg1 treatment significantly ameliorated depression-like behaviors in rats subjected to chronic unpredictable stress (CUS). Moreover, these CUS rats treated with Rg1 exhibited attenuated neuroinflammation, together with the suppression of Cx43 ubiquitination. In in vitro experiments, Rg1 reduced the secretion of inflammatory cytokines and the ubiquitination of Cx43 in lipopolysaccharide-induced glial cells. Furthermore, treatment with ubiquitin-proteasome inhibitor MG132 suppressing the ubiquitination of Cx43 ameliorated lipopolysaccharide-induced neuroinflammation. The results suggest that Rg1 attenuates depression-like behavioral performances in CUS-exposed rats; and the main mechanism of the antidepressant-like effects of Rg1 appears to involve protection against neuroinflammation via suppression of Cx43 ubiquitination. In conclusion, Rg1 could ameliorate neuroinflammation via suppression of Cx43 ubiquitination to attenuate depression, which represents the perspective of an innovative therapy of Rg1 in the treatment of inflammation-associated depression.

New Therapeutic Approaches to and Mechanisms of Ginsenoside Rg1 against Neurological Diseases

“…Research has confirmed that Rg1 can inhibit neuroinflammation in neurological diseases [ 63 , 65 ]. However, most studies focus on the mechanism of pro-inflammatory factors [ 63 , 65 , 66 ], and few studies examine anti-inflammatory factors [ 58 ]. In future research, we can further study the effect of Rg1 on anti-inflammatory factors in neurological diseases, and how Rg1 affects the balance between anti-inflammatory and proinflammatory factors to improve neurological diseases.…”

“…Rg1 reduced the level of intracellular adhesion molecule 1 (ICAM-1), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), as well as maintained the integrity of BBB permeability in neuroinflammation-induced behavioral deficits [ 65 ]. Studies have shown that Rg1 reduced the levels of IL-1β, TNF-α, caspase-1, IL-2, IL-6 and IL-18 via the suppression of Connexin43 (Cx43) ubiquitination in depression [ 66 ] ( Figure 3 ). Overall, there are few disease model studies on Rg1 inhibiting the neuroinflammatory response, and it is more about inhibiting the expression of inflammatory factors.…”

Connexin 43: An Interface Connecting Neuroinflammation to Depression

“…Likewise, Ginsenoside Rg1 is one of the constituents extracted from ginseng, with antidepressant and anti-inflammatory neuroprotective properties [ 159 ]. Ginsenoside Rg1 attenuates neuroinflammation by inhibiting Cx43 ubiquitination, thereby reducing depression [ 160 ]. Similarly, minocycline, an antibiotic, reduces the proinflammatory cytokines from activated microglia and relieves depression [ 161 ].…”

Ginsenoside Rg1 ameliorates sepsis-induced acute kidney injury by inhibiting ferroptosis in renal tubular epithelial cells

“…Ginsenoside Rg1, one of the most prominent active components in ginseng that is a distinguished herbal medicine, possesses antioxidant, antiaging, and immune and memory improving properties. [25][26][27][28] Compelling reports have unveiled the therapeutic effects of ginsenoside Rg1 on kidney-related diseases: for instance, ginsenoside Rg1 can protect human renal TECs from LPS-elicited apoptosis and inflammatory injury 29 ; ginsenoside Rg1 imposes protection on antiglomerular basement membrane glomerular nephritis through activation of the NRF2 pathway 30 ; ginsenoside Rg1 represses angiotensin II-triggered podocyte autophagy through the AMPK/mTOR/PI3K pathway. 31 Previous research has documented that ginsenoside Rg1 could protect against kidney injury by attenuating oxidative stress.…”