Selective Cyclooxygenase-2 Inhibitors in Preclinical Rodent Models of Depression and Post-traumatic Stress Disorder:
Alexey Sarapultsev1,2, Maria Komelkova1, Irina Utepova1,3
1Russian-Chinese Education and Research Center of System Pathology, South Ural State University, 76 Lenin Prospekt, Chelyabinsk 454080, Russia.
Abstract:
Depression and post-traumatic stress disorder (PTSD) are treatment-resistant neuropsychiatric conditions closely linked to chronic neuroinflammation. Given the limitations of current pharmacotherapies, selective cyclooxygenase-2 (COX-2) inhibitors have emerged as promising candidates for modulating neuroimmune and oxidative pathways. This systematic review evaluated the efficacy of selective COX-2 inhibitors in improving behavioral and neuroinflammatory outcomes in rodent models of chronic stress or systemic inflammation relevant to depression and PTSD. A comprehensive search was conducted across PubMed, Scopus, Web of Science, and other databases for in vivo rodent studies published between 2010 and 2025. Inclusion criteria required validated chronic stress or inflammation paradigms (≥7 days), selective COX-2 inhibitors, and reporting of quantitative behavioral and neuroinflammatory end points. Thirty-four studies met eligibility criteria and were synthesized both qualitatively and via targeted random-effects meta-analysis for depression-like behaviors. COX-2 inhibitors such as celecoxib, meloxicam, and etoricoxib reduced forced swim test immobility by approximately 40% and increased sucrose preference by 25-30%, effects comparable to or exceeding SSRIs. Reductions in IL-6, TNF-α, and COX-2 expression ranged from 30% to 60%, along with suppression of the NF-κB pathway and markers of glial activation (Iba-1, GFAP). Concurrent activation of antioxidant pathways via Nrf2/HO-1 led to elevated levels of SOD, GSH, and BDNF, which correlated with behavioral improvements. A pooled meta-analysis (n = 15 comparisons) revealed a large standardized effect size (Hedges' g = 3.19; 95% CI: 2.14-4.25; I2 = 92.2%) in favor of COX-2 inhibition. While findings consistently support these agents' antidepressant- and anxiolytic-like efficacy in chronic stress models, their translational potential is limited by male-restricted samples (91% of studies), underreporting of effect sizes, and a scarcity of long-term durability assessments. These results support continued investigation of COX-2 inhibitors as adjunctive treatments in stress-related psychiatric disorders, with an emphasis on sex-stratified analyses and standardized behavioral and molecular reporting.
Insights
Selective cyclooxygenase-2 (COX-2) inhibitors show significant promise for treating depression and PTSD by reducing neuroinflammation. These agents effectively improved behavioral and molecular outcomes in rodent models, suggesting potential as adjunctive therapies.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Depression and PTSD are complex neuropsychiatric disorders often linked to chronic neuroinflammation.
- Current pharmacotherapies have limitations, driving research into novel treatment strategies.
- Selective cyclooxygenase-2 (COX-2) inhibitors are being explored for their potential to modulate neuroimmune and oxidative stress pathways.
Purpose of the Study:
- To systematically review the efficacy of selective COX-2 inhibitors in rodent models of chronic stress or inflammation relevant to depression and PTSD.
- To evaluate the impact of COX-2 inhibitors on behavioral and neuroinflammatory outcomes.
- To synthesize findings from in vivo rodent studies using qualitative and meta-analytic approaches.
Main Methods:
- A comprehensive literature search was performed across major scientific databases for studies published between 2010 and 2025.
- Inclusion criteria focused on validated chronic stress/inflammation paradigms (≥7 days), selective COX-2 inhibitors, and quantitative behavioral/neuroinflammatory endpoints.
- Thirty-four studies were included, with meta-analysis conducted for depression-like behaviors.
Main Results:
- Selective COX-2 inhibitors significantly reduced depression-like behaviors (e.g., decreased immobility, increased sucrose preference) in rodent models.
- These agents markedly reduced key inflammatory markers (e.g., IL-6, TNF-α, COX-2 expression) and suppressed the NF-κB pathway.
- Upregulation of antioxidant pathways (Nrf2/HO-1) and neurotrophic factors (BDNF) correlated with behavioral improvements.
Conclusions:
- Selective COX-2 inhibitors demonstrate significant antidepressant- and anxiolytic-like effects in preclinical models of stress-related disorders.
- Findings support their potential as adjunctive treatments, particularly for conditions involving neuroinflammation.
- Further research should address sex-specific effects and long-term outcomes for translational application.
