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

Publication ,  Journal Article
Krishnamurthy, K; Huang, YZ; Harward, SC; Sharma, KK; Tamayo, DL; McNamara, JO
Published in: Ann Neurol
December 2019

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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Published In

Ann Neurol

DOI

EISSN

1531-8249

Publication Date

December 2019

Volume

86

Issue

6

Start / End Page

939 / 950

Location

United States

Related Subject Headings

  • Signal Transduction
  • Seizures
  • Protein Kinases
  • Protein Kinase Inhibitors
  • Neurology & Neurosurgery
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Kindling, Neurologic
 

Citation

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Krishnamurthy, K., Huang, Y. Z., Harward, S. C., Sharma, K. K., Tamayo, D. L., & McNamara, J. O. (2019). Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure. Ann Neurol, 86(6), 939–950. https://doi.org/10.1002/ana.25602
Krishnamurthy, Kamesh, Yang Zhong Huang, Stephen C. Harward, Keshov K. Sharma, Dylan L. Tamayo, and James O. McNamara. “Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure.Ann Neurol 86, no. 6 (December 2019): 939–50. https://doi.org/10.1002/ana.25602.
Krishnamurthy K, Huang YZ, Harward SC, Sharma KK, Tamayo DL, McNamara JO. Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure. Ann Neurol. 2019 Dec;86(6):939–50.
Krishnamurthy, Kamesh, et al. “Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure.Ann Neurol, vol. 86, no. 6, Dec. 2019, pp. 939–50. Pubmed, doi:10.1002/ana.25602.
Krishnamurthy K, Huang YZ, Harward SC, Sharma KK, Tamayo DL, McNamara JO. Regression of Epileptogenesis by Inhibiting Tropomyosin Kinase B Signaling following a Seizure. Ann Neurol. 2019 Dec;86(6):939–950.
Journal cover image

Published In

Ann Neurol

DOI

EISSN

1531-8249

Publication Date

December 2019

Volume

86

Issue

6

Start / End Page

939 / 950

Location

United States

Related Subject Headings

  • Signal Transduction
  • Seizures
  • Protein Kinases
  • Protein Kinase Inhibitors
  • Neurology & Neurosurgery
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Kindling, Neurologic