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

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      Publication Details (including relevant citation   information):

      Kato, Akihiko S, Burris, Kevin D, Gardinier, Kevin M, Gernert,   Douglas L, Porter, Warren J, Reel, Jon, Ding, Chunjin, Tu, Yuan,   Schober, Douglas A, Lee, Matthew R, Heinz, Beverly A, Fitch,   Thomas E, Gleason, Scott D, Catlow, John T, Yu, Hong, Fitzjohn,   Stephen M, Pasqui, Francesca, Wang, He, Qian, Yuewei, Sher,   Emanuele, Zwart, Ruud, Wafford, Keith A, Rasmussen, Kurt,   Ornstein, Paul L, Isaac, John T R, Nisenbaum, Eric S, Bredt,   David S, Witkin, Jeffrey M Nature Medicine  2016 22 (12) 1496-1501

      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.;

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