The COX-2/prostanoid signaling cascades in seizure disorders

ABSTRACT

Introduction：A robust neuroinflammatory response is a prevalent feature of multiple neurological disorders, including epilepsy and acute status epilepticus. One component of this neuroinflammatory reaction is the induction of cyclooxygenase-2 (COX-2), synthesis of several prostaglandins and endocannabinoid metabolites, and subsequent activation of prostaglandin and related receptors. Neuroinflammation mediated by COX-2 and its downstream effectors has received considerable attention as a potential target class to ameliorate the deleterious consequences of neurological injury.

Areas covered: Here we describe the roles of COX-2 as a major inflammatory mediator. In addition, we discuss the receptors for prostanoids PGE₂, prostaglandin D2, and PGF_2α as potential therapeutic targets for inflammation-driven diseases. The consequences of prostanoid receptor activation after seizure activity are discussed with an emphasis on the utilization of small molecules to modulate prostanoid receptor activity.

Expert opinion: Limited clinical trial experience is supportive but not definitive for a role of the COX signaling cascade in epileptogenesis. The cardiotoxicity associated with chronic coxib use, and the expectation that COX-2 inhibition will influence the levels of endocannabinoids, leukotrienes, and lipoxins as well as the prostaglandins and their endocannabinoid metabolite analogs, is shifting attention toward downstream synthases and receptors that mediate inflammation in the brain.

KEYWORDS:

• Cyclooxygenase-2
• endocannabinoid
• EP1
• EP2
• epileptogenesis
• NSAID
• prostaglandins
• seizures
• epilepsy

Article highlights

• COX-2 promotes inflammation via the synthesis of prostaglandins and endocannabinoid metabolites.

• Long-term treatment with NSAIDs might reduce the risk of developing epilepsy.

• Receptors for PGE₂, and potentially PGD₂ and PGF_2α, are potential therapeutic targets for epilepsy.

• Selective EP2 receptor antagonism following status epilepticus produces a number of beneficial effects.

• Activation of EP1 and FP exacerbates seizures via intracellular Ca²⁺ mobilization pathways.

• Brain PGD₂ and PGF_2α levels are remarkably elevated during seizures, the latter likely secondary to massive synthesis of PGE2.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by National Institutes of Health (NIH) grants NS097776, R21 NS101167 and U01 AG052460 awarded to R. Dingledine and T. Ganesh, respectively.