As has been shown the intracellular pathways of ghrelin

As has been shown, the intracellular pathways of ghrelin signaling have been studied previously. The PI3K-Akt signaling may play a role in the influence of ghrelin. One study found that ghrelin signaling in the ventral hippocampus stimulated learned and motivational aspects of feeding via PI3K-Akt signaling (Kanoski et al., 2013). A study of neuropathic pain demonstrated that ghrelin can alleviate pain through inhibition of the p38 mitogen-activated protein kinase (p38-MAPK) pathway (Zhou et al., 2014). Another study revealed, that ghrelin can inhibit mitochondrial dysfunction under high glucose/high lipid conditions, and suppress endothelial apoptosis via inhibiting JNK1/2 and p38 signaling (Liao et al., 2017). These studies hint, that p38-MAPK pathway may be one of the major intracellular signaling pathways of the ghrelin/GHSR system. As of now, there is no known role of this pathway in depression. However, the p38-MAPK is activated in response to various stress stimuli (Wang et al., 2007; Lizama et al., 2009; Peng et al., 2013), such as noise stress, heat stress and posttraumatic stress. The P38 activation depends on the phosphorylation of Thr180 and Tyr182 in the Thr-Gly-Tyr motif of the activation loop, so the phosphorylation of p38 (p-p38) represents the activation of the p38-MAPK signaling pathway (Zarubin and Han, 2005; Nebreda and Porras, 2000; Zhang et al., 2007). Inspired by the abovementioned findings, we hypothesize that social defeat stress can also activate the p38-MAPK signaling pathway and that ghrelin might possess antidepressant potential by inhibiting the p38-MAPK signaling pathway in GHSR-positive neurons. To clarify the role of ghrelin in the pathogenesis of depression, we first investigated, if endogenous ghrelin/GHSR system was altered after exposure to CSDS. As hippocampus (Shen et al., 2018; Roddy et al., 2018), amygdala (Yao et al., 2018) and prefrontal cortex (Wang et al., 2018; Xu et al., 2018) all seem to represent common herpes simplex virus 1 regions that potentially mediate depression- and anxiety-like behavior, we observed the role of GHSR in these brain areas. After that, we assessed the effects of GHSR knockdown in hippocampus on the behavior of mice under normal condition or CSDS. Then, we examined the effects of drug administration on the behavior of stressed mice, using exogenous ghrelin as well as the p38 inhibitor, SB203580. Lastly, we analyzed the hippocampal levels of p-p38 in stressed mice treated with either ghrelin or vehicle, and in GHSR-knockdown mice under normal or CSDS condition.
Methods
Results
Discussion
Conclusion The following are the supplementary data related to this article.
Ethics statement
Role of funding source The project was funded by the National Key Research and Development Program of China (2017YFB0403803), the National Natural Science Fund of China (81271500, 81473437, 81671349, and 81774444), the Development Project of Shanghai Peak Disciplines-Integrated Chinese and Western Medicine, the Shanghai Municipal Education Commission (Class II Plateau Disciplinary Construction Program for Medical Technology of SUMHS, 2018–2020), the Seed Fund of Shanghai University of Medicine and Health Sciences (E1-0200-18-201133) and the Hundred Teacher Talent Program of Shanghai University of Medicine and Health Sciences.
Contributors
Conflict of interest
Acknowledgements
Introduction Mitogen-activated protein kinase (MAPK) superfamily are members of serine/threonine protein kinase that play important roles in cellular response to extracellular stimuli [1]. This superfamily has four main subgroups including extracellular signal-regulated kinases (ERKs), c-jun N-terminal or stress-activated protein kinases (JNK/SAPK), ERK/big MAP kinase 1 (BMK1), and p38 MAPK [2,3]. p38 MAPK is involved in inflammation, environmental stresses and microbial infections in various organisms [[4], [5], [6]]. It has been demonstrated that p38 MAPK is activated during viral infection and replication in mammals [[7], [8], [9]]. Overexpression of p38 MAPK inhibits viral gene transcription and protein synthesis as well as apoptosis in fish cells [10]. So, p38 MAPK is probably involved in cellular immune responses to microbial infection in fish. On the other hand, fish is subjected to various environmental stresses such as ammonia stress which adversely impact fish immune function [11]. To date, there is little available information about the role of p38 MAPK in ammonia stress in fish.