Abstracts

Rationale: Epilepsy is frequently associated with cognitive and psychiatric comorbidities that degrade quality of life. In many pharmacoresistant patients these issues can be more debilitating than the seizures themselves. The mechanistic basis of cognitive comorbidities is suggested to involve sclerosis-associated neuronal death and/or neuroinflammation. Neuroinflammation is the consequence of several broad signaling cascades including cyclooxygenase-2 (COX-2). Our previous studies show that activation of the EP2 receptor for prostaglandin E2 appears responsible for blood-brain barrier leakage, monocyte infiltration, and much of the inflammatory reaction, neuronal injury and cognitive deficit that follows seizure-provoked COX-2 induction in brain.  The goals of the present study were to determine if our novel EP2 antagonist TG11-77 (J Med Chem 63:1032, 2020) relieves the early pathological consequences of status epilepticus (SE) and associated cognitive comorbidities, and to progress this compound towards IND and clinical trials for treatment of long-term cognitive deficits after SE.  _x000D_
Methods: Male C57BL/6CR mice were subject to 1 hr of SE induced by ip injection of pilocarpine, scored for seizure severity, weight recovery, and delayed mortality.  Surviving mice were randomized into EP2 antagonist and vehicle groups.  The EP2 antagonist or vehicle was administered in blinded fashion ip  4, 8, and 19 hours post-SE. One cohort of mice was sacrificed four days post-SE for neuropathological analysis. A separate cohort of mice was allowed to recover for 8-17 days before they were subject to cognitive testing in the Y-maze. IND-enabling ADMET, PK and DRF-tox studies were done by subcontract.

Results: EP2 antagonism, via TG11-77, reduced SE-induced microgliosis in the amygdala, CA1 hippocampus, and neocortex four days after SE, with a minimum effective dose of 8.8 mg/kg.  Interestingly, however, astrocytosis and neuronal injury were not alleviated by this EP2 antagonist. Strikingly, mice subject to the EP2 antagonist showed reduced delayed mortality and elimination of the Y-maze deficit after status epilepticus. Pharmacokinetics that guided these efficacy studies were conducted by subcontract. In vitro studies required to submit an investigational new drug (IND) application have been completed, and non-GLP dose range-finding toxicology in the rat revealed no overt, organ or histopathology signs of toxicity after 7 days’ oral administration of 1000 mg/kg/day._x000D_
Conclusions: Our findings provide additional proof-of-concept that EP2 antagonism after SE can alleviate multiple adverse effects including SE-induced cognitive decline. TG11-77 is poised to continue development towards the initial clinical test of the hypothesis that EP2 receptor modulation after SE can provide the first preventive treatment for one of the chief comorbidities of epilepsy.  Our study also likely underlies a more generalizable strategy for disease modification of acquired and genetic epilepsies, and perhaps other chronic CNS disorders driven substantially by inflammation.

Funding: 1UG3NS113879 (R.D. and T.G.), U01AG052460 (T.G.), Georgia Research Alliance (R.D.), Biolocity (T.G.), R01 NS112350 (NHV)