Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.

Abstract

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects. These findings demonstrate the first rationally discovered molecule targeting specific neural circuitries for therapeutic advantage.

• Authors: Akihiko S Kato, Kevin D Burris, Kevin M Gardinier, Douglas L Gernert, Warren J Porter, Jon Reel, Chunjin Ding, Yuan Tu, Douglas A Schober, Matthew R Lee, Beverly A Heinz, Thomas E Fitch, Scott D Gleason, John T Catlow, Hong Yu, Stephen M Fitzjohn, Francesca Pasqui, He Wang, Yuewei Qian, Emanuele Sher, Ruud Zwart, Keith A Wafford, Kurt Rasmussen, Paul L Ornstein, John T R Isaac, Eric S Nisenbaum, David S Bredt, Jeffrey M Witkin
• Journal: Nature medicine (Nat Med) Vol. 22 Issue 12 Pg. 1496-1501 (12 2016) ISSN: 1546-170X [Electronic] United States
• PMID: 27820603 (Publication Type: Journal Article)

Chemical References

• Anticonvulsants
• Benzothiazoles
• Cacng2 protein, rat
• Calcium Channels
• Convulsants
• LY3130481
• Nitriles
• Pyrazoles
• Pyridones
• Receptors, AMPA
• TARP gamma-8 protein, mouse
• cacng8 protein, rat
• perampanel
• Pentylenetetrazole

Topics

• Animals
• Anticonvulsants (adverse effects, pharmacology)
• Benzothiazoles (pharmacology)
• Calcium Channels (metabolism)
• Cerebellum (drug effects, metabolism)
• Convulsants (toxicity)
• Disease Models, Animal
• Dizziness (chemically induced)
• Epilepsy (chemically induced, drug therapy)
• Mice
• Nitriles
• Pentylenetetrazole (toxicity)
• Prosencephalon (drug effects, metabolism)
• Pyrazoles (pharmacology)
• Pyridones (adverse effects, pharmacology)
• Rats
• Receptors, AMPA (antagonists & inhibitors, metabolism)
• Seizures (chemically induced, drug therapy)