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A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.
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.
Type
Journal articleSubject
Amino Acid SequenceAnimals
Epilepsy
Female
Hippocampus
Humans
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Transgenic
Molecular Sequence Data
Peptide Fragments
Phospholipase C gamma
Rats
Rats, Sprague-Dawley
Receptor, trkB
Status Epilepticus
Uncoupling Agents
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https://hdl.handle.net/10161/11838Published Version (Please cite this version)
10.1016/j.neuron.2015.09.032Publication Info
Gu, Bin; Huang, Yang Zhong; He, Xiao-Ping; Joshi, Rasesh B; Jang, Wonjo; & McNamara,
James O (2015). A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced
by Status Epilepticus. Neuron, 88(3). pp. 484-491. 10.1016/j.neuron.2015.09.032. Retrieved from https://hdl.handle.net/10161/11838.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Xiao-Ping He
Assistant Professor of Neurology
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Yangzhong Huang
Assistant Research Professor of Neurobiology
The goal of my research is to elucidate the molecular and signaling mechanisms underlying
epilepsy, a common and commonly devastating neurological disorder. There are two major
objectives of my current work. I aim to understand the mechanisms by which brain-derived
neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB transform the brain
from normal to epileptic, a process termed epileptogenesis; and to develop peptide
and small molecule inhibitors of TrkB signaling for preven
James O'Connell McNamara Sr.
Duke School of Medicine Distinguished Professor in Neuroscience
Our goal is to elucidate the cellular and molecular mechanisms underlying epileptogenesis,
the process by which a normal brain becomes epileptic. The epilepsies constitute
a group of common, serious neurological disorders, among which temporal lobe epilepsy
(TLE) is the most prevalent and devastating. Many patients with severe TLE experienced
an episode of prolonged seizures (status epilepticus, SE) years prior to the onset
of TLE. Because induction of SE alone is
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