cAMP/PKA-CREB-BDNF signaling pathway in hippocampus mediates cyclooxygenase 2-induced learning/memory deficits of rats subjected to chronic unpredictable mild stress

Abstract

To investigate the mechanism of cyclooxygenase 2 (COX2) in learning and memory impairments in rats subjected to chronic unpredictable mild stress (CUMS), meloxicam was used intragastrically to inhibit the activity of cyclooxygenase 2. Moreover, cyclooxygenase 2 over-expressing or RNA interfere lentivirus was injected intraventricularly to increase or decrease the enzyme's expression, respectively. The body weights and sucrose consumption were used to analyze depressive behaviors, while the Morris water maze and step-down-type passive avoidance tests were carried out to evaluate the learning-memory functions. The levels of inflammatory cytokines were measured to estimate inflammation and the contents of cyclic adenosine monophosphate (cAMP) were used to measure the levels of the second messenger. Changes in cyclooxygenase 2 mRNA levels were analyzed using reverse transcription polymerase chain reaction. Moreover, the expression of cyclooxygenase 2, brain-derived neurotrophic factor (BDNF), prostaglandins receptor 3 (EP3), protein kinase A (PKA), cAMP response element binding protein (CREB), and phosphorylated CREB were estimated using immunohistochemical staining or western blotting. The results showed that CUMS led to significant depressive-like behaviors and learning and memory dysfunctions. Also, the cAMP levels decreased significantly, while levels of inflammatory cytokines and prostaglandins E2 increased significantly. The expressions of PKA, BDNF, phosphorylated CREB/CREB declined and cyclooxygenase 2 was increased. Meloxicam and cyclooxygenase 2 RNA interfere lentivirus reversed the changes caused by CUMS while cyclooxygenase 2-overexpressing lentivirus worsened these abnormalities. The findings also showed that CUMS increased cyclooxygenase 2 expression, which can cause learning and memory impairments, mainly through activating the hippocampal neuronal cAMP/PKA-CREB-BDNF signaling pathways.

Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

“…Highlighting the role of COX‐2 inhibition in neuroprotection, Luo, Kuang, Li, Ran, and Yang () inhibited COX‐2 signalling via two methods in chronically stressed rats: (a) meloxicam, a COX‐2 selective non‐steroidal anti‐inflammatory and (b) via RNA‐interference. COX‐2 inhibition reversed the pro‐inflammatory and anti‐neurotrophic changes induced by chronic stress.…”

“…Highlighting the role of COX-2 inhibition in neuroprotection, Luo, Kuang, Li, Ran, and Yang (2017) TNFα and NF-κB, as well as, the apoptotic marker caspase-3 in mice (Elnahas, Abou Zeid, Kawy, Hendawy, & Baher, 2016).…”

Pivotal role of cAMP‐PKA‐CREB signaling pathway in manganese‐induced neurotoxicity in PC12 cells

“…The prevailing view of the cAMP‐PKA‐CREB signaling pathway is closely related to cognitive deficits . Several mechanisms for this have been proposed, including the regulation by γ‐aminobutyric acid‐B receptor, regulation of transcription factor myocyte‐enhancer factor 2, activation downstream of NF‐kB signaling pathway and related proinflammatory cytokines, increased downstream of proapoptotic proteins (Bcl‐2 family and caspase) expression, and reduction of BDNF expression .…”

“…Neuronal apoptosis is considered to be one of the mechanisms of Mn‐induced neurotoxicity, which involves Bcl‐2 family‐mediated mitochondrial dysfunction, cytochrome c release, and caspases' activation . Recent evidence suggests that cAMP‐PKA‐CREB signaling regulates apoptosis and is associated with cognitive function . As a second messenger of intracellular signal, cAMP can activate PKA, which can lead to phosphorylation of CREB (pCREB) on Ser133 .…”

“…12,13 Recent evidence suggests that cAMP-PKA-CREB signaling regulates apoptosis and is associated with cognitive function. [14][15][16][17] As a second messenger of intracellular signal, cAMP can activate PKA, which can lead to phosphorylation of CREB (pCREB) on Ser133. 18,19 These processes have been demonstrated as important for the induction and persistence of long-term memory and long-term potentiation.…”