Integrative Perspectives on COX-2 Signaling and Selective Inhibitors in Central Nervous System Disorders: A Narrative...

Central nervous system disorders include various neurodegenerative and psychiatric conditions characterized by progressive neuronal damage, synaptic dysfunction, and chronic neuroinflammation, affecting millions worldwide. This group includes Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Multiple Sclerosis (MS), Major Depressive Disorder (MDD), and epilepsy, among others. Recent studies have emphasized the significant role of Cyclooxygenase-2 (COX-2), an inducible enzyme in the arachidonic acid pathway, in maintaining neuroinflammatory cascades that worsen these conditions.

For this review, we gathered and carefully analyzed published literature related to COX-2 signaling in CNS disorders. We reviewed preclinical studies, animal models, and clinical trials to understand how COX-2 contributes to disease mechanisms and whether selective inhibitors show real therapeutic promise.

Inflammatory cytokines or excitotoxic insults upregulate COX-2 and promote the formation of prostaglandins, including PGE2. These mediators subsequently trigger the activation of microglia and astrocytes, cytokine release, oxidative stress, disruption of the blood-brain barrier, and neuronal apoptosis. Despite variations in disease-specific features, the mechanisms dependent on COX-2 are generally consistent across these disorders.

The consistent involvement of COX-2-driven neuroinflammation across multiple CNS disorders suggests it could be a promising therapeutic target. However, failures in some clinical trials highlight the complexity of translating preclinical findings into patient care. This may be due to the stage-dependent expression of COX-2, the multifunctional roles of the enzyme in normal brain function, and the cardiovascular risks associated with long-term COX-2 inhibition. These factors must be carefully considered in future research and drug development.

COX-2 plays a central role in driving neuroinflammation and disease progression in AD, PD, ALS, schizophrenia, MS, MDD, and epilepsy. Selective COX-2 inhibitors show promising neuroprotective potential, especially in early stages or in combination therapies, but inconsistent efficacy and cardiovascular risks necessitate safer next- generation inhibitors.