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. 2016 Jan 21:12:219-27.
doi: 10.2147/NDT.S90960. eCollection 2016.

cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats

Xu Liu  1 , Haibiao Guo  2 , Mohammad Daud Som Sayed  3 , Yang Lu  3 , Ting Yang  4 , Dongsheng Zhou  5 , Zhongming Chen  5 , Haitao Wang  2 , Chuang Wang  3 , Jiangping Xu  2
Affiliations

cAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats

Xu Liu et al. Neuropsychiatr Dis Treat. .

Abstract

Objectives: GEBR-7b, a potential phosphodiesterase 4D inhibitor, has been shown to have memory-enhancing effects in rodents. However, it is still unknown whether GEBR-7b also has the antidepressant-like effects in rats. Herein, we examined the potential of GEBR-7b to attenuate depression-like behaviors in the rat model of depression induced by chronic unpredictable stress (CUS). Next, we also investigated the alterations of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) catalytic subunit (PKAca), cAMP response element-binding (CREB), and glutamate transporter 1 (GLT1) levels produced by GEBR-7b in the rats model of depression.

Methods: Effects of GEBR-7b on CUS (35 days)-induced depression-like behaviors were examined by measuring immobility time in the forced swimming test (FST). Hippocampal cAMP levels were examined by enzyme-linked immunosorbent assay, whereas PKAca, phosphorylation of CREB (pCREB), CREB, and GLT1 in the hippocampus of rats were subjected to Western blot analysis.

Results: CUS exposure caused a depression-like behavior evidenced by the increased immobility time in FST. Depression-like behavior induced by CUS was accompanied by a significant increased GLT, decreased cAMP, PKAca, pCREB activities in hippocampus. However, repeated GEBR-7b administration significantly reversed CUS-induced depression-like behavior and changes of cAMP/PKA/CREB/GLT1 signaling. No alteration was observed in locomotor activity in open field test.

Conclusion: These findings indicate that GEBR-7b reversed the depression-like behaviors induced by CUS in rats, which is at least in part mediated by modulating cAMP, PKAca, pCREB, and GLT1 levels in the hippocampus of rats, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by CUS.

Keywords: GEBR-7b; cAMP response element-binding protein; cyclic adenosine monophosphate; glutamate transporter 1; phosphodiesterase 4D; phosphorylation of CREB; protein kinase Aca.

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Figures

Figure 1
Figure 1
Effect of chronic GEBR-7b treatment on CUS-induced depression-like behaviors in rats. Notes: (A) Schematic representation of the experimental procedure for CUS and treatments in rats. CUS rats were exposed to one stressor per day for 21 days, and then received 14 days of GEBR-7b or vehicle injections during which CUS continued. (B) OFT: exploratory activities (total distance traveled) were evaluated in a 5-minute test session. (C) OFT: movement velocity was evaluated in a 5-minute test session. (D) FST: time spent for immobility was scored for a 5-minute-test session. Results are expressed as mean ± SEM (n=8 per group). *P<0.01, compared to nonstressed rats treated with vehicle; **P<0.05. Abbreviations: CUS, chronic unpredictable stress; OFT, open field test; FST, forced swimming test; SEM, standard error of the mean; ip, intraperitoneal injection.
Figure 2
Figure 2
Chronic GEBR-7b treatment reverses chronic unpredictable stress (CUS)-induced reduction of cAMP levels in the hippocampus of rats. Notes: Data shown are means ± SEM of eight animals/group, and these were analyzed using one-way ANOVA followed by Newman–Keuls tests. *P<0.01 vs nonstressed rats treated with vehicle; **P<0.01 versus stressed rats treated with vehicle. Abbreviations: CUS, chronic unpredictable stress; cAMP, cyclic adenosine monophosphate; SEM, standard error of the mean; ANOVA, analysis of variance.
Figure 3
Figure 3
Effect of chronic GEBR-7b treatment on expression of PKAca, pCREB, CREB, and GLT1 in the hippocampus of rats. Notes: (A) Representative immunoblots of PKAca, pCREB, CREB, and GLT1 detected by Western blotting with tissues from the hippocampus; the rest of the panels are the quantification of the immunoblotting bands of PKAca (B), pCREB (C), CREB (D), and GLT1 (E). Data shown are mean ± SEM of eight animals/group and were analyzed using one-way ANOVA followed by Newman–Keuls tests. *P<0.01 vs nonstressed rats treated with vehicle; **P<0.01 vs stressed rats treated with vehicle. Abbreviations: PKAca, protein kinase A catalytic subunit; pCREB, phosphorylation of cAMP response element-binding; CREB, cAMP response element-binding; GLT1, glutamate transporter 1; cAMP, cyclic adenosine monophosphate; CUS, chronic unpredictable stress; SEM, standard error of the mean.
Figure 4
Figure 4
Diagram of signaling pathway indicating the possible mechanism by which GEBR-7b reversed CUS-induced depression-like behaviors in rats. Notes: GEBR-7b inhibited the PDE4D activity, and further increased the levels cAMP, PKA, and pCREB, resulting in the upregulation of GLT1 in hippocampus of rats. → indicates activate/induce. →l indicates inhibit/antagonism. Abbreviations: CUS, chronic unpredictable stress; PDE4D, phosphodiesterase 4D; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; pCREB, phosphorylation of cAMP response element-binding; GLT1, glutamate transporter 1; PKAca, protein kinase A catalytic subunit; CBP, CREB binding protein.
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