"Targeting Inflammation in Neurologic Disease"

Presented by Dr. Raymond Dingledine, Professor, Department of Pharmacology and Chemical Biology at the Emory University School of Medicine.

Abstract: Cyclooxygenase-2 (COX-2) is rapidly induced in neurons by seizures or after injury and orchestrates one of the chief inflammatory signaling cascades in the brain.  To explore the role of COX-2 in seizure-induced neuropathology we first created a mouse in which COX-2 is conditionally ablated in selected forebrain neurons. Our results indicate that neuronal COX-2 induction promotes delayed neurodegeneration of hippocampal neurons, intensifies a broad inflammatory reaction in the hippocampus involving numerous cytokines and other inflammatory mediators, is essential for development of a leaky blood– brain barrier after seizures, and causes delayed mortality after status epilepticus. These findings point to a profound role of neuronal COX-2 expression in seizure-induced neuropathologies. We then developed novel, potent and selective competitive antagonists of the prostaglandin EP2 receptor that have sufficient plasma half-life and brain penetration to be useful in proof-of-concept animal models. We found that EP2 antagonism phenocopies the effects of conditional, spatially-limited COX-2 ablation in neurons. Conditional cell-specific ablation of EP2 supports a strong role for activation of EP2 on microglia and/or monocytes in these effects. These studies demonstrate a profound role for EP2 activation in COX-2 related pathologies and are highlighting the importance of neuroinflammation in epilepsy.Cyclooxygenase-2 (COX-2) is rapidly induced in neurons by seizures or after injury and orchestrates one of the chief inflammatory signaling cascades in the brain.  To explore the role of COX-2 in seizure-induced neuropathology we first created a mouse in which COX-2 is conditionally ablated in selected forebrain neurons. Our results indicate that neuronal COX-2 induction promotes delayed neurodegeneration of hippocampal neurons, intensifies a broad inflammatory reaction in the hippocampus involving numerous cytokines and other inflammatory mediators, is essential for development of a leaky blood– brain barrier after seizures, and causes delayed mortality after status epilepticus. These findings point to a profound role of neuronal COX-2 expression in seizure-induced neuropathologies. We then developed novel, potent and selective competitive antagonists of the prostaglandin EP2 receptor that have sufficient plasma half-life and brain penetration to be useful in proof-of-concept animal models. We found that EP2 antagonism phenocopies the effects of conditional, spatially-limited COX-2 ablation in neurons. Conditional cell-specific ablation of EP2 supports a strong role for activation of EP2 on microglia and/or monocytes in these effects. These studies demonstrate a profound role for EP2 activation in COX-2 related pathologies and are highlighting the importance of neuroinflammation in epilepsy.