Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism
Selective pharmacological blockade of forebrain excitatory AMPA receptors that express the TARP γ-8 subunit enables antiepileptic therapy in rodent models of epilepsy without inducing motor impairments associated with currently used antiepileptic drugs. Pharmacological manipulation of specific neura...
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| Published in | Nature medicine Vol. 22; no. 12; pp. 1496 - 1501 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.12.2016
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Selective pharmacological blockade of forebrain excitatory AMPA receptors that express the TARP γ-8 subunit enables antiepileptic therapy in rodent models of epilepsy without inducing motor impairments associated with currently used antiepileptic drugs.
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
1
, and their antagonists are antiepileptic
2
. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment
3
,
4
. 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
5
, 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. |
|---|---|
| AbstractList | Selective pharmacological blockade of forebrain excitatory AMPA receptors that express the TARP γ-8 subunit enables antiepileptic therapy in rodent models of epilepsy without inducing motor impairments associated with currently used antiepileptic drugs.
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
1
, and their antagonists are antiepileptic
2
. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment
3
,
4
. 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
5
, 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. 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. 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 gamma -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 gamma -8, but not gamma -2 (cerebellum) or other TARP members. Two amino acid residues unique to gamma -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. 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.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. |
| Author | Pasqui, Francesca Wang, He Burris, Kevin D Nisenbaum, Eric S Porter, Warren J Ornstein, Paul L Schober, Douglas A Lee, Matthew R Witkin, Jeffrey M Heinz, Beverly A Qian, Yuewei Catlow, John T Sher, Emanuele Gernert, Douglas L Zwart, Ruud Ding, Chunjin Kato, Akihiko S Tu, Yuan Reel, Jon Fitzjohn, Stephen M Gardinier, Kevin M Rasmussen, Kurt Yu, Hong Bredt, David S Fitch, Thomas E Wafford, Keith A Isaac, John T R Gleason, Scott D |
| Author_xml | – sequence: 1 givenname: Akihiko S surname: Kato fullname: Kato, Akihiko S email: katoak@lilly.com organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 2 givenname: Kevin D surname: Burris fullname: Burris, Kevin D organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 3 givenname: Kevin M surname: Gardinier fullname: Gardinier, Kevin M organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 4 givenname: Douglas L surname: Gernert fullname: Gernert, Douglas L organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 5 givenname: Warren J surname: Porter fullname: Porter, Warren J organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 6 givenname: Jon surname: Reel fullname: Reel, Jon organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 7 givenname: Chunjin surname: Ding fullname: Ding, Chunjin organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 8 givenname: Yuan surname: Tu fullname: Tu, Yuan organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 9 givenname: Douglas A surname: Schober fullname: Schober, Douglas A organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 10 givenname: Matthew R surname: Lee fullname: Lee, Matthew R organization: Applied Molecular Evolution, Eli Lilly and Company – sequence: 11 givenname: Beverly A surname: Heinz fullname: Heinz, Beverly A organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 12 givenname: Thomas E surname: Fitch fullname: Fitch, Thomas E organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 13 givenname: Scott D surname: Gleason fullname: Gleason, Scott D organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 14 givenname: John T surname: Catlow fullname: Catlow, John T organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 15 givenname: Hong surname: Yu fullname: Yu, Hong organization: Lilly Research Laboratory, Eli Lilly and Company, Present addresses: Janssen PRD, San Diego, California, USA (H.Y. and D.S.B.); School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK (S.M.F.); College of Pharmacy, Roosevelt University, Schaumburg, Illinois, USA (P.L.O.); Wellcome Trust, London, UK (J.T.R.I.) – sequence: 16 givenname: Stephen M surname: Fitzjohn fullname: Fitzjohn, Stephen M organization: Lilly UK, Eli Lilly and Company, Present addresses: Janssen PRD, San Diego, California, USA (H.Y. and D.S.B.); School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK (S.M.F.); College of Pharmacy, Roosevelt University, Schaumburg, Illinois, USA (P.L.O.); Wellcome Trust, London, UK (J.T.R.I.) – sequence: 17 givenname: Francesca surname: Pasqui fullname: Pasqui, Francesca organization: Lilly UK, Eli Lilly and Company – sequence: 18 givenname: He surname: Wang fullname: Wang, He organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 19 givenname: Yuewei surname: Qian fullname: Qian, Yuewei organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 20 givenname: Emanuele surname: Sher fullname: Sher, Emanuele organization: Lilly UK, Eli Lilly and Company – sequence: 21 givenname: Ruud surname: Zwart fullname: Zwart, Ruud organization: Lilly UK, Eli Lilly and Company – sequence: 22 givenname: Keith A surname: Wafford fullname: Wafford, Keith A organization: Lilly UK, Eli Lilly and Company – sequence: 23 givenname: Kurt surname: Rasmussen fullname: Rasmussen, Kurt organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 24 givenname: Paul L surname: Ornstein fullname: Ornstein, Paul L organization: Lilly Research Laboratory, Eli Lilly and Company, Present addresses: Janssen PRD, San Diego, California, USA (H.Y. and D.S.B.); School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK (S.M.F.); College of Pharmacy, Roosevelt University, Schaumburg, Illinois, USA (P.L.O.); Wellcome Trust, London, UK (J.T.R.I.) – sequence: 25 givenname: John T R surname: Isaac fullname: Isaac, John T R organization: Lilly UK, Eli Lilly and Company, Present addresses: Janssen PRD, San Diego, California, USA (H.Y. and D.S.B.); School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK (S.M.F.); College of Pharmacy, Roosevelt University, Schaumburg, Illinois, USA (P.L.O.); Wellcome Trust, London, UK (J.T.R.I.) – sequence: 26 givenname: Eric S surname: Nisenbaum fullname: Nisenbaum, Eric S organization: Lilly Research Laboratory, Eli Lilly and Company – sequence: 27 givenname: David S surname: Bredt fullname: Bredt, David S organization: Lilly Research Laboratory, Eli Lilly and Company, Present addresses: Janssen PRD, San Diego, California, USA (H.Y. and D.S.B.); School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK (S.M.F.); College of Pharmacy, Roosevelt University, Schaumburg, Illinois, USA (P.L.O.); Wellcome Trust, London, UK (J.T.R.I.) – sequence: 28 givenname: Jeffrey M surname: Witkin fullname: Witkin, Jeffrey M email: jwitkin@lilly.com organization: Lilly Research Laboratory, Eli Lilly and Company |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27820603$$D View this record in MEDLINE/PubMed |
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| Snippet | Selective pharmacological blockade of forebrain excitatory AMPA receptors that express the TARP γ-8 subunit enables antiepileptic therapy in rodent models of... Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are... |
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| SubjectTerms | 692/617/375/178 Animals Anticonvulsants - adverse effects Anticonvulsants - pharmacology Benzothiazoles - pharmacology Biomedicine Calcium Channels - metabolism Cancer Research Cerebellum - drug effects Cerebellum - metabolism Convulsants - toxicity Disease Models, Animal Dizziness - chemically induced Epilepsy - chemically induced Epilepsy - drug therapy Infectious Diseases letter Metabolic Diseases Mice Molecular Medicine Neurosciences Pentylenetetrazole - toxicity Prosencephalon - drug effects Prosencephalon - metabolism Pyrazoles - pharmacology Pyridones - adverse effects Pyridones - pharmacology Rats Receptors, AMPA - antagonists & inhibitors Receptors, AMPA - metabolism Seizures - chemically induced Seizures - drug therapy |
| Title | Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism |
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