Abstract
Carbon monoxide (CO), a byproduct of heme catalyzed by heme oxygenase (HO), has been reported to exert antioxidant and anti-inflammatory actions, and to produce significant neuroprotective effects. The potential effects of CO and even HO on depressive-like behaviors are still poorly understood. Utilizing several approaches including adeno-associated virus (AAV)-mediated overexpression of HO-1, systemic CO-releasing molecules (CO-RMs), CO-rich saline or CO gas treatment procedures in combination with hydrogen peroxide (H2O2)-induced PC12 cell injury model, and lipopolysaccharide (LPS)-induced depression mouse model, the present study aimed to investigate the potential antidepressant- and anxiolytic-like effects of endogenous and exogenous CO administration in vivo and in vitro. The results of in vitro experiments showed that both CO-RM-3 and CO-RM-A1 pretreatment blocked H2O2-induced cellular injuries by increasing cell survival and decreasing cell apoptosis and necrosis. Similar to the effects of CO-RM-3 and CO-RM-A1 pretreatment, AAV-mediated HO-1 overexpression in the dorsal hippocampus produced significant antidepressant-like activities in mice under normal conditions. Further investigation showed that the CO gas treatment significantly blocked LPS-induced depressive- and anxiety-like behaviors in mice. Taken together, our results suggest that the activation of HO-1 and/or exogenous CO administration produces protective effects and exerts antidepressant- and anxiolytic-like effects. These data uncover a novel function of the HO-1/CO system that appears to be a promising therapeutic target for the treatment of depression and anxiety.
Highlights
Major depressive disorder (MDD) is one of the most common mental illnesses worldwide, which can cause suicide, disability, problem behaviors, and limitations in day-to-day activities (Trivedi et al, 2006; Kaufman, 2018; Domschke and Gottschalk, 2019)
A post hoc analysis revealed that heme oxygenase (HO)-1 protein levels were significantly increased in the dorsal hippocampus area of mice microinfused with AAVHO-1 virus as compared to those of NAV (p 0.001) or associated virus (AAV)-GFP–treated groups (p < 0.001)
These results indicated that the dorsal hippocampus HO-1 overexpression induced antidepressantlike activities in mice that were evident in the forced swimming test (FST) and TST
Summary
Major depressive disorder (MDD) is one of the most common mental illnesses worldwide, which can cause suicide, disability, problem behaviors, and limitations in day-to-day activities (Trivedi et al, 2006; Kaufman, 2018; Domschke and Gottschalk, 2019). CO Produces Antidepressant-Like Effects treatments in MDD patients (Dowlati et al, 2010; Martinowich et al, 2013; Hodes et al, 2015; Goldsmith et al, 2016; Liu et al, 2017c). In rodents, both chronic mild stress (CMS) exposure and systemic lipopolysaccharide (LPS) administration can induce inflammatory responses, increase significant depressive- and anxiety-like behaviors, and cause memory impairments (Yin et al, 2019), which can be blocked by some antioxidant and anti-inflammatory agents such as flavonoid and sulfur dioxide (SO2) (Hritcu et al, 2017; Shi et al, 2020). Whether CO has a direct effect on depressive- and anxiety-like behaviors and its mechanisms of action are still elusive
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