Mechanisms of Seizure-Induced Inflammation of the Brain: Many Possible Roles for Neuronal COX-2.

Commentary It is well established that seizures, particularly status epilepti-cus (SE), induce upregulation of cyclooxygenase-2 (COX-2) in both neurons and non-neuronal cells (1, 2). COX-2 plays a role in seizure-induced leukocyte infiltration, astrogliosis, microg-lial activation, and breakdown of the blood-brain barrier (BBB); thus, COX-2 is clearly an important component of brain inflammation. COX-2 is also thought to play an important role in seizure-induced neurodegeneration; in fact, COX-2 inhibitors generally reduce neuronal death and provide neuroprotection. Although COX-2 is thought to be expressed primarily in non-neuronal cells, it is also expressed in neurons; furthermore, seizures strongly enhance neuronal COX-2 (nCOX-2) expression. An important question addressed by the present papers is the role of nCOX-2 in brain inflammatory mechanisms, which was studied in a mouse model in which COX-2 was conditionally ablated in specific forebrain neurons. One important Cyclooxygenase-2 (COX-2), a source of inflammatory mediators and a multifunctional neuronal modulator, is rapidly induced in select populations of cortical neurons after status epilepticus. The consequences of rapid activity-triggered induction of COX-2 in neurons have been the subject of much study and speculation. To address this issue directly, we created a mouse in which COX-2 is conditionally ablated in selected forebrain neurons. Results following pilocarpine-induced status epilepticus indicate that neuronal COX-2 promotes early neuroprotection and then delayed neurode-generation of CA1 pyramidal neurons, promotes neurodegeneration of nearby somatostatin interneurons in the CA1 stratum oriens and dentate hilus (which themselves do not express COX-2), intensifies a broad inflammatory reaction involving numerous cytokines and other inflammatory mediators in the hippocampus, and is essential for development of a leaky blood-brain barrier after seizures. These findings point to a profound role of seizure-induced neuronal COX-2 expression in neuropathologies that accompany epileptogenesis. With interest waning in the use of cyclooxygenase-2 (COX-2) inhibitors for inflammatory disease, prostaglandin receptors provide alternative targets for the treatment of COX-2–mediated pathological conditions in both the periphery and the central nervous system. Activation of prostaglandin E2 receptor (PGE2) subtype EP2 promotes inflammation and is just beginning to be explored as a therapeutic target. To better understand physiological and pathological functions of the prostaglandin EP2 receptor, we developed a suite of small molecules with a 3-aryl-acrylamide scaffold as selective EP2 antagonists. The 12 most potent compounds displayed competitive antagonism of the human EP2 receptor with KB 2–20 nM in Schild regression analysis and 268-to 4,730-fold selectivity over the prostaglandin EP4 receptor. A brain-permeant compound completely suppressed the …