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Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

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Review

Neurobiology and Therapeutic Potential of Cyclooxygenase-2 (COX-2) Inhibitors for Inflammation in Neuropsychiatric Disorders

Rickinder Sethi et al. Front Psychiatry.

Abstract

Neuropsychiatric disorders, such as depression, bipolar disorder, schizophrenia, obsessive-compulsive disorder, and neurodevelopmental disorders such as autism spectrum disorder, are associated with significant illness burden. Accumulating evidence supports an association between these disorders and inflammation. Consequently, anti-inflammatory agents, such as the cyclooxygenase-2 inhibitors, represent a novel avenue to prevent and treat neuropsychiatric illness. In this paper, we first review the role of inflammation in psychiatric pathophysiology including inflammatory cytokines' influence on neurotransmitters, the hypothalamic-pituitary-adrenal axis, and microglial mechanisms. We then discuss how cyclooxygenase-2-inhibitors influence these pathways with potential therapeutic benefit, with a focus on celecoxib, due to its superior safety profile. A search was conducted in PubMed, Embase, and PsychINFO databases, in addition to Clinicaltrials.gov and the Stanley Medical Research Institute trial registries. The results were presented as a narrative review. Currently available outcomes for randomized controlled trials up to November 2017 are also discussed. The evidence reviewed here suggests cyclooxygenase-2 inhibitors, and in particular celecoxib, may indeed assist in treating the symptoms of neuropsychiatric disorders; however, further studies are required to assess appropriate illness stage-related indication.

Keywords: autism spectrum disorder; bipolar disorder; cyclooxygenase-2 inhibitors; depression; inflammation; obsessive compulsive disorder; psychiatry; schizophrenia.

Figures

Figure 1
Figure 1
COX-2 contributes to inflammation through PGE2 and IL-6 and is selectively inhibited by celecoxib and rofecoxib. Activated by inflammatory cytokines including PGE2 and IL-6, AA (the precursor substrate of the COX-2 pathway) is extracted from phospholipid membranes by phospholipases such as cPLA2. COX-2 then drives production of prostaglandins including prostaglandin H2 (PGH2), which in turn is converted to PGE2 via PGE synthase. An accumulation of PGE2 leads to increased IL-6 (along with other cytokines) contributing to the inflammatory milieu, further potentiation of the pathway and neurotoxicity contributing to psychopathology. Celecoxib and rofecoxib exert selective inhibition of COX-2 reducing this pathway’s contribution to inflammation mediated neurotoxicity (→ = activates/increases, ⊥ = inhibits).

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