Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus

Abstract

As a prominent inflammatory effector of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) mediates brain inflammation and injury in many chronic central nervous system (CNS) conditions including seizures and epilepsy, largely through its receptor subtype EP2. However, EP2 receptor activation might also be neuroprotective in models of excitotoxicity and ischemia. These seemingly incongruent observations expose the delicacy of immune and inflammatory signaling in the brain, thus the therapeutic window for quelling neuroinflammation might vary with injury type and target molecule. Here, we identify a therapeutic window for EP2 antagonism to reduce delayed mortality and functional morbidity after status epilepticus (SE) in mice. Importantly, treatment must be delayed relative to SE onset to be effective, a finding that could be explained by the time-course of COX-2 induction after SE and compound pharmacokinetics. A large number of inflammatory mediators were upregulated in hippocampus after SE with COX-2 and IL-1β temporally leading many others. Thus, EP2 antagonism represents a novel anti-inflammatory strategy to treat SE with a tightly-regulated therapeutic window.

Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus

“…We have previously shown that, during the 24 h following SE, rodents quickly lose 10-20% of their body weight and then gradually begin to recover in the following days (6,8,39). As expected, animals subject to SE lost ∼13% of their body weight in the 24 h after SE onset, independent of Ccr2 genotype (Fig.…”

“…CCL2 levels increase in the brain after SE (8,9,(53)(54)(55), and SE-induced induction of CCL2 mRNA is rapid in hippocampal tissue, increasing more than 10-fold 30 min after SE onset and continuing to increase to nearly 100-fold 4 d after SE (39). Earlier studies reported that astrocytes are the cellular source of CCL2 after brain injury (56).…”

“…5A). Quantitative real-time PCR (qRT-PCR) was performed on hippocampal tissue to measure the levels of five inflammatory mediators previously shown to be induced after SE (30,39). The basal mRNA levels of these inflammatory mediators were nearly identical in saline solution-treated wild-type and Ccr2 knockout animals (Fig.…”

Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application

“…The pathophysiological interactions among the various inflammatory molecules, and the sequence of events leading to their induction, have not yet been dissected out due to the complexity of the inflammatory cascade; recent review articles describe in detail the available knowledge [58,64,73–77]. Briefly, within 30–60 min of the onset of SE in adult mouse and rat, elevated IL-1β, TNF-α, IL-6 transcript levels are found in the hippocampus or forebrain concomitant with a rise in neuronal COX-2 protein [78–83]. These changes are followed shortly by morphological evidence of activation of microglia, reactive gliosis and infiltrating monocytes [59,82,84,85].…”

Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats

“…In animal models of organophosphorus agent exposure, survivors exhibit a number of consequences such as weight loss, neuroinflammation, neurodegeneration, long-term cognitive deficits and the development of spontaneous recurrent seizures (SRS) (Binukumar et al, 2011; Chen 2012; Gilat et al, 2005; Joosen et al, 2009; Pan et al, 2012; Raveh et al, 2003; Reddy & Kuruba, 2013; Rojas et al, 2015; Tattersall 2009; Tilson et al, 1990). Short-term inhibition of the EP2 receptor following SE in rats and mice induced by DFP or the muscarinic receptor agonist pilocarpine attenuates the consequences of status epilepticus that manifest within hours to days following the initial insult, including neuroinflammation, neuronal injury and breakdown of the blood-brain barrier (Jiang et al, 2013; Jiang et al, 2015; Rojas et al, 2015). Whether EP2 inhibition also ameliorates the long-term consequences of DFP-induced SE such as cognitive deficits has not been investigated and is the focus of the current study.…”