Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induced status epilepticus

Abstract

Exposure to high levels of organophosphorus compounds (OP) can induce status epilepticus (SE) in humans and rodents via acute cholinergic toxicity, leading to neurodegeneration and brain inflammation. Currently there is no treatment to combat the neuropathologies associated with OP exposure. We recently demonstrated that inhibition of the EP2 receptor for PGE2 reduces neuronal injury in mice following pilocarpine-induced SE. Here, we investigated the therapeutic effects of an EP2 inhibitor (TG6-10-1) in a rat model of SE using diisopropyl fluorophosphate (DFP). We tested the hypothesis that EP2 receptor inhibition initiated well after the onset of DFP-induced SE reduces the associated neuropathologies. Adult male Sprague-Dawley rats were injected with pyridostigmine bromide (0.1 mg/kg, sc) and atropine methylbromide (20 mg/kg, sc) followed by DFP (9.5 mg/kg, ip) to induce SE. DFP administration resulted in prolonged upregulation of COX-2. The rats were administered TG6-10-1 or vehicle (ip) at various time points relative to DFP exposure. Treatment with TG6-10-1 or vehicle did not alter the observed behavioral seizures, however six doses of TG6-10-1 starting 80-150 min after the onset of DFP-induced SE significantly reduced neurodegeneration in the hippocampus, blunted the inflammatory cytokine burst, reduced microglial activation and decreased weight loss in the days after status epilepticus. By contrast, astrogliosis was unaffected by EP2 inhibition 4 d after DFP. Transient treatments with the EP2 antagonist 1 h before DFP, or beginning 4 h after DFP, were ineffective. Delayed mortality, which was low (10%) after DFP, was unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor within a time window that coincides with the induction of cyclooxygenase-2 by DFP is neuroprotective and accelerates functional recovery of rats.

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.…”

“…These admittedly sparse clinical findings are consistent with the much more extensive animal literature in demonstrating a florid inflammatory response of the brain to SE (5). We and others have provided evidence in animal models of epilepsy that quenching inflammation after SE can provide neuroprotection, prevent BBB opening, alleviate morbidity, and rescue behavioral deficits (6)(7)(8)(9)(10).…”

“…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).…”

“…One possibility is that neuron-released prostaglandin E 2 , a product of cyclooxygenase-2 (COX-2), induces microglial CCL2 expression via EP2 receptors. Indeed, genetic removal of neuronal COX-2 or EP2 antagonism can mitigate the induction of CCL2 mRNA in the brain (6,8,9) or in purified microglia (57). Another possibility is that neuronal ATP release increases CCL2 in microglia via P2X7 receptors (58).…”

EP2 Receptor Signaling Regulates Microglia Death

“…Targeting EP2 signaling pathways may be an efficient approach to control the degree of microglial activation, thus reducing chronic inflammation and brain damage in neurologic diseases. The therapeutic window for EP2 antagonists opens after seizures with the neuronal induction of COX-2 and consequent production of PGE 2 Rojas et al, 2015). Our data suggest that the therapeutic window might close toward the end of active inflammation, when microglial death is needed to resolve inflammation.…”