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Increasing aspartoacylase in the central amygdala: the common mechanism of gastroprotective effects of monoamine-based antidepressants against stress
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  • kaiyun Yao,
  • Linyu Cao,
  • Hongwan Ding,
  • Yinge Gao,
  • Tiegang Li,
  • Guibin Wang,
  • Jianjun Zhang
kaiyun Yao
China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica
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Linyu Cao
China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica
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Hongwan Ding
China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica
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Yinge Gao
China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica
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Tiegang Li
China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica
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Guibin Wang
China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica

Corresponding Author:[email protected]

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Jianjun Zhang
Institute of Materia Medica (IMM), Chinese Academy of Medical Sciences & Peking Union Medical College
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Abstract

Background and purpose Monoamine-based antidepressants can protect from stress-induced gastric ulcer. Central nucleus of amygdala (CeA) has been shown to modulate the severity of stress ulcers in rats. Proton magnetic resonance spectroscopy (1H-MRS) provided a non-invasive tool to identify the duration-related neurometabolites of CeA in the process of gastroprotective of antidepressants. Experimental Approach We used 1H-MRS to explore the specific neurometabolite in CeA which was correlated with severity of gastric ulcer induced by water immersion restraint stress (WIRS) in rats, and further determined which kinds of enzymes modulating this molecule were involved in the gastroprotective effect of antidepressants. We started with SNRI duloxetine and then extended to the other three types of monoamine-based antidepressants to probe the potential generalized molecular mechanisms. Key Results Duloxetine decreased NAA/creatine in CeA after 6 h of WIRS, whereas vehicle had no effect. Gastric ulcer index was negatively correlated with reduced NAA/creatine. Furthermore, intra-CeA infusion of NAA aggravated WIRS-induced gastric mucosa damage. NAA catabolizing enzyme aspartoacylase (ASPA) was the only enzyme downregulated by 0.5-h WIRS and upregulated by duloxetine. Overexpressing ASPA in CeA alleviated the gastric ulcer caused by WIRS. Pretreatment with other monoamine-based antidepressants including fluoxetine, amitriptyline and moclobemide all increased ASPA expression in the CeA in the same model. Conclusion and Implications Collectively, monoamine-based antidepressants exerted gastroprotective effects against stress by increasing ASPA to hydrolyze NAA in CeA. Our work demonstrated ASPA as a joint target more than monoamine regulation for this kind of drugs.