Abstract
This study was designed to investigate the effect of the cortical cyclooxygenase-2 (COX2) pathway on depressive behaviour in rats. Meloxicam, COX2 overexpressed lentivirus and COX2 RNAi lentivirus were administered to Sprague-Dawley rats subjected to chronic unpredictable mild stress (CUMS). Behaviour tests, biochemistry and immunohistochemistry methods, enzyme-linked immunosorbent assays, western blotting and reverse transcription polymerase chain reactions were used to evaluate the changes in rat behaviour and the cortical COX2 pathway. CUMS rats showed depressive–like behaviours. The superoxide dismutase activity and cyclic adenosine monophosphate (cAMP) contents were significantly decreased, the contents of malondialdehyde, prostaglandin E2 (PGE2) and inflammatory cytokines were significantly increased. The expressions of protein kinase A (PKA) and cAMP response element-binding protein (CREB) were decreased, and the levels of brain-derived neurotrophic factor (BDNF) and COX2 were significantly increased. Meloxicam and COX2 RNAi lentivirus significantly alleviated the abnormalities induced by CUMS, while COX2 overexpressed lentivirus aggravated these abnormalities. Our results indicated that the cortical COX2 pathway was activated in CUMS rats. Inhibition of COX2 activity/expression can obviously improve depressive behaviours in CUMS rats. Upregulating COX2 expression can increase the susceptibility of rats to CUMS. An imbalance in the cortical COX2-PGE2-cAMP/PKA-CREB-BDNF signalling pathway participates in the pathogenic mechanism of depression.
Highlights
Cyclooxygenase-2 (COX2) is the key enzyme for the production of a series of inflammatory cytokines
Our previous study showed that chronic unpredictable mild stress (CUMS) causes significant depressive behaviour in rats and that the oral administration of meloxicam, a COX2 inhibitor, can relieve depressive symptoms, alleviate damage of hippocampal nerve cells and up-regulate the expression of neural plasticity-related factors, such as synaptophysin (SYP), brain-derived neurotrophic factor (BDNF) post-synaptic density 95 (PSD-95) and 5-hydroxytryptamine(5-HT)1A receptor, in the hippocampus[11]
Group, the administration of sertraline and meloxicam significantly increased the activity of superoxide dismutase (SOD) and the concentration of cyclic adenosine monophosphate (cAMP), and significantly decreased the contents of MDA, prostaglandin E2 (PGE2), tumour necrosis factor–α (TNF-α) and IL-1β. *P < 0.05 and **P < 0.01 vs the normal group, respectively. #P < 0.05 and ##P < 0.01 vs the CUMS group, respectively
Summary
Cyclooxygenase-2 (COX2) is the key enzyme for the production of a series of inflammatory cytokines. Our previous study showed that chronic unpredictable mild stress (CUMS) causes significant depressive behaviour in rats and that the oral administration of meloxicam, a COX2 inhibitor, can relieve depressive symptoms, alleviate damage of hippocampal nerve cells and up-regulate the expression of neural plasticity-related factors, such as synaptophysin (SYP), brain-derived neurotrophic factor (BDNF) post-synaptic density 95 (PSD-95) and 5-hydroxytryptamine(5-HT)1A receptor, in the hippocampus[11]. These results together suggest that the hippocampal COX2 pathway may be a target for the development of therapeutic drugs for depression. It is worth studying the pathogenesis of depression through observing the changes in the COX2 pathway
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