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

Neuropharmacology. 2015 Jun;93:15-27. doi: 10.1016/j.neuropharm.2015.01.017. Epub 2015 Feb 3.

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.

Keywords: COX-2; DFP; EP2; Hippocampus; Inflammation; Neurodegeneration; Organophosphorus; PGE2; Status epilepticus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • Behavior, Animal / drug effects
  • Body Weight / drug effects
  • Chemokines / genetics
  • Chemokines / metabolism
  • Cholinesterase Inhibitors / toxicity*
  • Cyclooxygenase 2 / metabolism
  • Disease Models, Animal
  • Gliosis / chemically induced
  • Hippocampus / pathology
  • Indoles / pharmacokinetics
  • Indoles / therapeutic use
  • Isoflurophate / toxicity*
  • Male
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacokinetics
  • Neuroprotective Agents / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP2 Subtype / antagonists & inhibitors
  • Receptors, Prostaglandin E, EP2 Subtype / metabolism*
  • Recovery of Function / drug effects*
  • Status Epilepticus / chemically induced*
  • Status Epilepticus / drug therapy
  • Status Epilepticus / pathology
  • Time Factors

Substances

  • Chemokines
  • Cholinesterase Inhibitors
  • Indoles
  • Neuroprotective Agents
  • Receptors, Prostaglandin E, EP2 Subtype
  • TG6-10-1
  • Isoflurophate
  • Cyclooxygenase 2
  • Acetylcholinesterase