Abstract
Monoamine-based antidepressants can prophylactically protect against stress-induced gastric ulcers. Although the central nucleus of amygdala (CeA) has been shown to modulate the severity of stress ulcers, little is known about the molecular mechanisms underlying the gastroprotective effect of this kind of drugs. Here, we first used proton magnetic resonance spectroscopy, a non-invasive tool, to explore the change of neurometabolites of the CeA of rats pretreated with the duloxetine of selective serotonin-norepinephrine reuptake inhibitors during 6 h of water-immersion restraint stress (WIRS). Duloxetine decreased N-acetyl-aspartate/creatine ratio (NAA/creatine) in CeA after WIRS, which was paralleled by the amelioration of gastric lesions. Meanwhile, the gastric ulcer index was negatively correlated with reduced NAA/creatine. Furthermore, the intra-CeA infusion of NAA aggravated WIRS-induced gastric mucosa damage, which suggested the crucial role of reduced NAA. Western blotting was performed to identify the specific enzymes responsible for the change of the contents of NAA at 0.5 h/3 h/6 h after WIRS, considering the preventative gastric protection of duloxetine. The NAA-catabolizing enzyme aspartoacylase (ASPA) was the only enzyme downregulated by 0.5 h WIRS and upregulated by duloxetine. Moreover, overexpressing ASPA in CeA alleviated stress ulcers. Additionally, all of the other three monoamine-based antidepressants, the fluoxetine of selective serotonin reuptake inhibitors, the amitriptyline of tricyclic agents, and the moclobemide of MAOs, increased ASPA expression in CeA. Together, these results indicate that increasing ASPA to hydrolyze NAA in CeA is a common mechanism of gastroprotective effects against stress exerted by monoamine-based antidepressants, and ASPA is a shared target more than monoamine regulation for this kind of drugs.
Highlights
A disproportionate sensitivity to stress or excessive intensity of stressors may overwhelm the allostatic capacity, leading to poor adaptation, producing physiological and psychological abnormality, and resulting in organ damage and diseases such as gastric ulceration, depression, and posttraumatic stress disorder (McEwen 2008)
The data presented here showed that pretreatment with duloxetine significantly reduced NAA/Cre in the central nucleus of amygdala (CeA) after 6 h of water immersion restraint stress (WIRS), and the change of NAA/Cre in CeA was negatively correlated with the gastric ulcer index
The upregulation of ASPA may enhance the hydrolysis of NAA, leading to a decrease in NAA, which may be one of the common mechanisms underlying gastroprotective effects from WIRS by monoamine-based antidepressants
Summary
A disproportionate sensitivity to stress or excessive intensity of stressors may overwhelm the allostatic capacity, leading to poor adaptation, producing physiological and psychological abnormality, and resulting in organ damage and diseases such as gastric ulceration, depression, and posttraumatic stress disorder (McEwen 2008). Mucosal microbleedings and erosions or even gastric ulceration occurred as a typical stress-induced organ injury. Pretreatment with multiple monoamine-based antidepressants such as the tricyclic agent (TCA) amitriptyline, selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and fluoxetine, and the selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine has been shown to protect gastric mucosa damage caused by water immersion restraint stress (WIRS) (Khotib et al, 2019; Ji et al, 2012; Sen et al, 2002; Gabry et al, 2002). The methods of drug discovery are crucial to find a new active compound for the medication of diseases and disorders (Zhao et al, 2021; Xu et al, 2021; Ghanadian et al, 2020)
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