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Neuron. 2015 Nov 4;88(3):484-91. doi: 10.1016/j.neuron.2015.09.032. Epub 2015 Oct 17.

A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.

Author information

1
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
2
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
3
Department of Electrical and Computer Engineering, Duke University, Durham, NC 27710, USA.
4
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: jmc@neuro.duke.edu.

Abstract

The BDNF receptor tyrosine kinase, TrkB, underlies nervous system function in both health and disease. Excessive activation of TrkB caused by status epilepticus promotes development of temporal lobe epilepsy (TLE), revealing TrkB as a therapeutic target for prevention of TLE. To circumvent undesirable consequences of global inhibition of TrkB signaling, we implemented a novel strategy aimed at selective inhibition of the TrkB-activated signaling pathway responsible for TLE. Our studies of a mouse model reveal that phospholipase Cγ1 (PLCγ1) is the dominant signaling effector by which excessive activation of TrkB promotes epilepsy. We designed a novel peptide (pY816) that uncouples TrkB from PLCγ1. Treatment with pY816 following status epilepticus inhibited TLE and prevented anxiety-like disorder yet preserved neuroprotective effects of endogenous TrkB signaling. We provide proof-of-concept evidence for a novel strategy targeting receptor tyrosine signaling and identify a therapeutic with promise for prevention of TLE caused by status epilepticus in humans.

PMID:
26481038
PMCID:
PMC4636438
DOI:
10.1016/j.neuron.2015.09.032
[Indexed for MEDLINE]
Free PMC Article

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