Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure.

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2019-12

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Krishnamurthy, Kamesh
Huang, Yang Zhong
Harward, Stephen C
Sharma, Keshov K
Tamayo, Dylan L
McNamara, James O

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Abstract

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.

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10.1002/ana.25602

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Krishnamurthy, Kamesh, Yang Zhong Huang, Stephen C Harward, Keshov K Sharma, Dylan L Tamayo and James O McNamara (2019). Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure. Annals of neurology, 86(6). pp. 939–950. 10.1002/ana.25602 Retrieved from https://hdl.handle.net/10161/19539.

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