Antiseizure effects of TrkB kinase inhibition
Open accessAbstract
Summary: Objective: The principal molecular targets of conventional antiseizure drugs consist of ligand‐gated and voltage‐gated ion channels and proteins subserving synaptic function. Inhibition of the receptor tyrosine kinase TrkB limits epileptogenesis, but its effect on individual seizures is unknown. We sought to determine whether inhibition of TrkB kinase exerts an antiseizure effect. Methods: We utilized the kindling model in combination with an inducible conditional knockout of the TrkB gene (Act‐Cre ER TrkBflox/flox mice treated with tamoxifen), and also with a chemical‐genetic approach in which mice carry a TrkB kinase with a phenylalanine to alanine substitution of residue 616 (TrkBF616A), which allows inhibition of the kinase by a blood–brain barrier permeable small molecule, 1′‐naphthylmethyl‐4‐amino‐1‐tert‐butyl‐3‐(p‐methylphenyl)pyrazolo[3,4‐d]pyrimidine (1 NMPP 1). Results: Following induction of kindling, reduction of TrkB protein levels in Act‐Cre ER TrkBflox/flox mice treated with tamoxifen was associated with reduced severity of behavioral seizures evoked by stimulation. Treatment with 1 NMPP 1 for 2 weeks following induction of kindling reversibly elevated both focal electrographic and generalized seizure thresholds in TrkBF616A, but not wild‐type (WT), mice. In contrast to kindled animals, treatment of naive TrkBF616A mice for 2 weeks had no detectable effect on electrographic seizure threshold (EST). Significance: This study provides proof of concept of a novel molecular target for antiseizure drugs, namely the receptor tyrosine kinase TrkB. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
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Transient inhibition of the BDNF receptor TrkB after seizure induction prevents the development of temporal lobe epilepsy.
“Other studies have shown that transient inhibition of the BDNF receptor TrkB after seizure induction prevents the development of temporal lobe epilepsy [186, 187].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [187]
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Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation
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- Authors
- Liu, G., Kotloski, R. J., & McNamara, J. O.
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- McNamara, James O.
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2014-06-05
- Volume
- 55
- Issue
- 8
- Pages
- 1264-1273
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- PMC
- PMC4126863
- OpenAlex
- W1996433749
- Cited by
- 27
- References
- 19
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 1 · 2014: 1
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS056217)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- antiepileptic drugs, kindling, receptor tyrosine kinase, conditional knockout mice, epilepsy, kinase inhibitors
- MeSH terms
- Animals, Anticonvulsants, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Protein Kinases, Protein-Tyrosine Kinases, Seizures, Treatment Outcome, Receptor, trkB, Protein Kinase Inhibitors, Mice
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