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

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.