Celecoxib ameliorates diabetic neuropathy by decreasing apoptosis and oxidative stress in dorsal root ganglion neurons via the miR‑155/COX‑2 axis

Abstract

Celecoxib (CXB) is the only clinical cyclooxygenase-2 (COX-2) inhibitor. Oral administration of CXB in experimental diabetic mice effectively relieved the symptoms of diabetic neuropathy (DN); however, the molecular mechanism remains unclear. The present study aimed to investigate the potential molecular mechanisms of CXB in the treatment of DN. An in vitro cellular model of DN was produced by stimulating dorsal root ganglion (DRG) neurons with high glucose. Cell viability and apoptosis were assessed by Cell Counting Kit-8 assays and flow cytometry, respectively. Reactive oxygen species (ROS) kits, ELISA kits and western blotting were used to determine oxidative cellular damage. The expression level of microRNA (miR)-155 was analyzed by reverse transcription-quantitative PCR. The starBase database and dual-luciferase assays were performed to predict and determine the interaction between miR-155 and COX-2. Protein expression of neurotrophic factors, oxidative stress-related proteins and COX-2 were analyzed by western blotting. Incubation with high glucose led to a decrease in DRG neuron cell viability, facilitated apoptosis, downregulated NGF and BDNF expression, increased ROS and MDA generation and decreased SOD activity. Treatment with CXB significantly protected DRG neurons against high glucose-evoked damage. CXB promoted the expression of miR-155 and COX-2 was revealed to be a direct target of miR-155. Inhibition of COX-2 enhanced the protective effect of CXB on DRG neurons and that treatment with an miR-155 inhibitor partially rescued this effect. The present study demonstrated the involvement of the miR-155/COX-2 axis in the protective effect of CXB against high glucose-induced DN.

Comprehensive Analysis of N6-Methyladenosine Regulators in the Subcluster Classification and Drug Candidates Prediction of Severe Obstructive Sleep Apnea

“…Abdulaziz A Alzahrani demonstrated that β-adrenoceptor blockade propranolol decreased respiratory frequency and abolished the CIH-mediated increase in vascular sympathetic nerve density. Similarly, several studies have shown that cyclooxygenase inhibitors can attenuate inflammatory responses by decreasing oxidative stress ( Cheng et al, 2021 ). For example, Tissot Low showed that IH-induced lung inflammation could be completely abolished by daily intraperitoneal injection of ibuprofen (a cyclooxygenase inhibitor) ( Cheng et al, 2021 ).…”

“…Similarly, several studies have shown that cyclooxygenase inhibitors can attenuate inflammatory responses by decreasing oxidative stress ( Cheng et al, 2021 ). For example, Tissot Low showed that IH-induced lung inflammation could be completely abolished by daily intraperitoneal injection of ibuprofen (a cyclooxygenase inhibitor) ( Cheng et al, 2021 ). Therefore, we speculate that cyclooxygenase inhibitors can improve OSA by inhibiting oxidative stress which needs to be demonstrated experimentally.…”

Celecoxib activates autophagy by inhibiting the mTOR signaling pathway and prevents apoptosis in nucleus pulposus cells

“…IL-1β and CXB might change ROS catalysis of the superoxide dismutase (SOD) to a different exent in the cytosol and mitochondira, and result in a discrepancy between consequent intracellular and mitochondrial ROS [ 33 , 34 ]. It was found that CXB affects ROS production variably in several studies, and altered mitochondrial function in a different context should be responsible for the difference [ 35 , 36 ]. Mitochondria are the primary sources of ROS, while pathological factors such as inflammation and hypoxia affect complex II of the mitochondrial respiratory chain and NADPH oxidase (NOX) activity.…”

“…It was proposed that overactive matrix metalloproteinases (MMP) induced by IL-1β lead to the structural change of intervertebral discs [26]. Furthermore, IL-1β promotes blood vessel and nerve ingrowth, followed by leukocyte infiltration and pain (35). In addition to IL-1β, other inflammatory cytokines including IL-6, IL-17, and TNF were also characterized in IDD.…”

Selective COX-2 Inhibitors: Road from Success to Controversy and the Quest for Repurposing

“…Another finding showed celecoxib to down-regulate the hippocampal COX-2 expression and up-regulate the BDNF-TrkB pathway to reverse memory deficits in a diabetic rat model [ 80 ]. In addition to that, celecoxib was found to ameliorate diabetic neuropathy via the inhibition of oxidative stress and apoptosis through the modulation of miR-155 in dorsal root ganglion neurons [ 81 ].…”