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Published on: September 15, 2011
Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure
Kamesh Krishnamurthy1, Yang Zhong Huang1, Stephen C Harward2
1Department of Neurobiology, Duke University, Durham, NC.
Objective:
Temporal lobe epilepsy (TLE) is a devastating disease in which seizures persist in 35% of patients despite optimal use of antiseizure drugs. Clinical and preclinical evidence implicates seizures themselves as one factor promoting epilepsy progression. What is the molecular consequence of a seizure that promotes progression? Evidence from preclinical studies led us to hypothesize that activation of tropomyosin kinase B (TrkB)-phospholipase-C-gamma-1 (PLCγ1) signaling induced by a seizure promotes epileptogenesis.
Methods:
To examine the effects of inhibiting TrkB signaling on epileptogenesis following an isolated seizure, we implemented a modified kindling model in which we induced a seizure through amygdala stimulation and then used either a chemical-genetic strategy or pharmacologic methods to disrupt signaling for 2 days following the seizure. The severity of a subsequent seizure was assessed by behavioral and electrographic measures.
Results:
Transient inhibition of TrkB-PLCγ1 signaling initiated after an isolated seizure limited progression of epileptogenesis, evidenced by the reduced severity and duration of subsequent seizures. Unexpectedly, transient inhibition of TrkB-PLCγ1 signaling initiated following a seizure also reverted a subset of animals to an earlier state of epileptogenesis. Remarkably, inhibition of TrkB-PLCγ1 signaling in the absence of a recent seizure did not reduce severity of subsequent seizures.
Interpretation:
These results suggest a novel strategy for limiting progression or potentially ameliorating severity of TLE whereby transient inhibition of TrkB-PLCγ1 signaling is initiated following a seizure. ANN NEUROL 2019;86:939-950.
Insights
Transiently inhibiting tropomyosin kinase B (TrkB)-phospholipase-C-gamma-1 (PLCγ1) signaling after a seizure can limit epilepsy progression. This approach may offer a new strategy for treating temporal lobe epilepsy (TLE).
Area of Science:
- Neuroscience
- Epilepsy Research
- Molecular Signaling
Background:
- Temporal lobe epilepsy (TLE) is a neurological disorder characterized by recurrent seizures.
- Approximately 35% of TLE patients experience persistent seizures despite medication.
- Seizures themselves may contribute to epilepsy progression, a process known as epileptogenesis.
Purpose of the Study:
- To investigate the role of tropomyosin kinase B (TrkB)-phospholipase-C-gamma-1 (PLCγ1) signaling in seizure-induced epileptogenesis.
- To determine if inhibiting TrkB-PLCγ1 signaling after a seizure can prevent or reverse epilepsy progression.
Main Methods:
- A modified kindling model was used, inducing an isolated seizure via amygdala stimulation.
- TrkB-PLCγ1 signaling was transiently inhibited for two days post-seizure using chemical-genetic or pharmacologic methods.
- Seizure severity and duration were assessed using behavioral and electrographic measures.
Main Results:
- Transient inhibition of TrkB-PLCγ1 signaling post-seizure reduced the severity and duration of subsequent seizures.
- This inhibition also appeared to revert some animals to an earlier stage of epileptogenesis.
- Inhibition of TrkB-PLCγ1 signaling without a recent seizure did not affect seizure severity.
Conclusions:
- Transient inhibition of TrkB-PLCγ1 signaling following a seizure represents a potential therapeutic strategy for TLE.
- This approach may limit epilepsy progression and ameliorate seizure severity.
- Targeting TrkB-PLCγ1 signaling offers a novel avenue for TLE treatment.
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