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Assessment of Memory Function in Pilocarpine-induced Epileptic Mice
Published on: June 4, 2020
Novel EP2 Antagonist Attenuates Microgliosis and Memory Deficits in Pilocarpine-Induced Status Epilepticus Mice
Thota Ganesh1, Soheila Pourkhodadad1, Paola Heman-Bozadas1
1Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd, Atlanta, Georgia 30322, United States.
Abstract:
EP2 receptors promote neuroinflammation in several central nervous system diseases including status epilepticus (SE). Our laboratory has been optimizing selective small-molecule antagonists for EP2 receptors to determine their functional role in neuropathology and behavioral deficits in SE models, with a goal of developing an EP2 antagonist for clinical use. Through lead-optimization, we identified a novel brain- penetrant compound BPN-37440, which possesses excellent EP2 potency, selectivity against other prostanoid receptors, demonstrates anti-inflammatory actions in the BV2-hEP2 cellular model, and exhibits suitable in vitro ADME and in vivo PK properties. A brief exposure of BPN-37440 after SE onset in mice attenuated microgliosis in the amygdala, cortex, and hippocampus CA3 region 4 days following recovery from SE. Moreover, memory deficits were prevented in mice at 1-1.5 months following SE. The results validate the notion that neuroinflammation promoted by EP2 exacerbates behavioral deficits, supporting further exploration of EP2 antagonists in the clinical setting.
Insights
A novel compound, BPN-37440, targets EP2 receptors to reduce neuroinflammation and prevent memory loss after status epilepticus (SE) in mice, supporting potential clinical use.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- EP2 receptors contribute to neuroinflammation in central nervous system diseases like status epilepticus (SE).
- Developing selective EP2 receptor antagonists is a therapeutic goal for neuropathology.
- Optimizing small-molecule antagonists requires assessing potency, selectivity, and pharmacokinetic properties.
Purpose of the Study:
- To identify and characterize a novel brain-penetrant EP2 receptor antagonist.
- To evaluate the efficacy of the antagonist in mitigating SE-induced neuropathology and behavioral deficits.
- To support the clinical development of EP2 antagonists for SE treatment.
Main Methods:
- Lead optimization of EP2 receptor antagonists.
- In vitro assays for EP2 potency, selectivity, and anti-inflammatory action (BV2-hEP2 cellular model).
- In vivo studies in SE mouse models to assess neuroinflammation (microgliosis) and memory deficits.
Main Results:
- Identified BPN-37440, a potent and selective brain-penetrant EP2 antagonist with favorable ADME/PK properties.
- BPN-37440 administration post-SE attenuated microgliosis in key brain regions (amygdala, cortex, hippocampus).
- Treatment with BPN-37440 prevented memory deficits in mice up to 1.5 months after SE.
Conclusions:
- Neuroinflammation mediated by EP2 receptors exacerbates behavioral deficits in SE.
- BPN-37440 demonstrates therapeutic potential for treating SE-related neuroinflammation and cognitive impairment.
- These findings support further clinical investigation of EP2 antagonists for status epilepticus.
