Abstract
BackgroundNeuroinflammation has recently emerged as a critical risk factor in the pathophysiology of depression. However, the underlying molecular mechanisms and the development of novel therapeutic strategies as means to target these inflammatory pathways for use in the treatment of depression remain unresolved. In the present study, we aimed to investigate the molecular events of neuroinflammation as related to its induction of depression-like behaviors.MethodsChronic unpredictable mild stress (CUMS) or lipopolysaccharide (LPS) was used to induce depression-like behaviors in rats. The inflammatory factors and related proteins were verified by RT-PCR, immunoblotting, and immunofluorescence assay. In vivo intracerebral injection of adenovirus-associated virus (AAV) in rats was used to overexpress or block the function of the β form of the calcium/calmodulin-dependent protein kinase type II (βCaMKII). In vivo intracerebroventricular injection of SB203580 was used to block p38 mitogen-activated protein kinase (MAPK). Finally, the prostaglandin E2 (PGE2) concentration was verified by using enzyme-linked assay kit.ResultsThe expression of cyclo-oxygenase (COX)-2, which is responsible for production of the pro-inflammatory factor PGE2 and thus glial activation, was increased in the CA1 hippocampus in a rat model of depression. Further, the βCaMKII in CA1 was significantly upregulated in depressed rats, while antidepressant treatment downregulated this kinase. Overexpression of βCaMKII via infusion of a constructed AAV-βCaMKII into the CA1 region resulted in phosphorylation of the p38 MAPK and the activating transcription factor 2 (ATF2). These effects were accompanied by an enhanced activity of the COX-2/PGE2 pathway and effectively induced core symptoms of depression. Conversely, knockdown of βCaMKII within the CA1 region reversed these inflammation-related biochemical parameters and significantly rescued depression symptoms.ConclusionThese results demonstrate that βCaMKII can act as a critical regulator in depression via activating neuroinflammatory pathways within the CA1 region. Moreover, this study provides new perspectives on molecular targets and drug therapies for future investigation in the treatment of depression.
Highlights
Neuroinflammation has recently emerged as a critical risk factor in the pathophysiology of depression
Whether activating transcription factor 2 (ATF2) functions as a downstream molecule of βCaMΚΙΙ to upregulate COX-2 transcription and facilitate inflammatory responses related to depression remains unknown. Based on this background information, in the present study, we investigated whether dysregulation of βCaMKII, a process that is linked to activation of COX2/ prostaglandin E2 (PGE2)-driven inflammatory pathways is involved in the genesis and progression of depression
Taken together with results obtained from the associated virus (AAV) virus injection experiments, these results indicate that p38 mitogen-activated protein kinase (MAPK) may be a critical downstream molecular target of βCaMKII in modulating the COX-2/PGE2 pathway and behavioral responses related to depression
Summary
Neuroinflammation has recently emerged as a critical risk factor in the pathophysiology of depression. The identification of novel inflammatory system targets as therapeutic strategies for the treatment of psychiatric disorders, like MDD, represents an essential area of current investigation. Results from clinical studies have indicated that these inflammatory markers are frequently maintained at persistently elevated levels in patients with MDD and are often associated with the duration or severity of the mood disorder [2]. Such observations support the significance of preventing the release of pro-inflammatory cytokines as a potential therapeutic approach to improve depressive symptoms and stress resilience
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