Antidepressant-like Effect of Merazin Hydrate Depends on NO/ERK by Suppressing Its Downstream NF-κB or Nonactivating CREB/BDNF in Mouse Hippocampus

Abstract

Merazin hydrate (MH), an essential ingredient of Fructus aurantii, has been identified to have an antidepressant-like effect. However, the molecular mechanisms of MH modulate depressive behavior are largely uncharacterized. Here, in lipopolysaccharide-induced mice, we identified that a single administration of MH recovered depressive behaviors and down-regulated the expressions of neuronal nitric oxide synthase (nNOS) in the hippocampus after 1 day. Activation of nNOS by l-arginine led to depressive behaviors, and inhibition of nNOS contributed to antidepressive behaviors. Notably, MH only reversed the expression of nNOS’s downstream NF-κB and not the CREB/BDNF pathway in the hippocampus, and MH’s antidepressant-like effects were prevented by Asatone (an agonist of NF-κB) and not H89 (an antagonist of CREB). MH also normalized the expressions of GFAP and IB-1 in dentate gyrus in the hippocampus and inflammatory factors such as IL-1β, IL-10, and TNF-α in serum. Overall, our studies reveal the molecular mechanisms of MH’s antidepressant-like effect.

Merazin Hydrate Produces Rapid Antidepressant Effects Depending on Activating mTOR Signaling by Upregulating Downstream Synaptic Proteins in the Hippocampus

“…The results showed that LH increased all of them significantly, which were all reversed by a single administration of MH at 2 h [Figure A–C; ANOVA, eNOS: F (3, 31) = 12.00, p < 0.001; IL-10: F (3, 31) = 8.25, p = 0.004; TNF-α: F (3, 31) = 26.35, p < 0.001], which was similar to ketamine. The results were consistent with our previous studies, which were revealed in LPS-induced mice in serum . Mounting evidence suggests that inflammation may play a key role in the etiology of depression .…”

“…Previously, we found that MH was capable of producing rapid antidepressant-like effects in lipopolysaccharide (LPS)-induced mice in the hippocampus, which depended on reliving neuroinflammation . However, the rapid antidepressant-like effects of MH are similar to those of some classic rapid antidepressant drugs, such as ketaminestill unclear.…”

“…Previously, we found that MH was capable of producing rapid antidepressant-like effects in lipopolysaccharide (LPS)-induced mice in the hippocampus, which depended on reliving neuroinflammation. 16 However, the rapid antidepressant-like To further determine the rapid antidepressant effects of MH, we used chronic mild stress (CMS) model to identify. The results showed that a single administration of MH (9.18 mg/ kg) was significantly capable of reversing the immobility times both in the TST and FST at 2 h, which were also obviously increased by CMS, similar to ketamine [Figure 3B,C In the study, we used two classic depressive models to test the rapid antidepressant-like effects of MH.…”

“…The results were consistent with our previous studies, which were revealed in LPS-induced mice in serum. 16 Mounting evidence suggests that inflammation may play a key role in the etiology of depression. 20 Antiinflammatory drugs may be a useful antidepressant therapy or an adjunct to the conventional therapies currently available.…”

“…Merazin hydrate (MH), one of the main ingredients of Fructus Aurantii (FRA), has been identified to be capable of rapid antidepressant-like effects in inflammatory depressive models in our previous research, 16 which downregulated the inflammatory pathway in the hippocampus. However, the rapid antidepressant-like effects of MH by regulating classic antidepressant molecular signaling, like mTOR signaling, were still unclear.…”