Antiseizure effects of TrkB kinase inhibition

• Published in: Epilepsia (Copenhagen) 2014-08, Vol.55 (8), p.1264-1273
• Main Authors: Liu, Gumei, Kotloski, Robert J, McNamara, James O.
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - therapeutic use; Epilepsy; Kindling; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Protein Kinase Inhibitors - therapeutic use; Protein Kinases - metabolism; Protein-Tyrosine Kinases; Receptor, trkB; Seizure; Seizures - drug therapy; Seizures - enzymology; Treatment; Treatment Outcome; TrkB
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.12671

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‐CreER 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 (1NMPP1). Results Following induction of kindling, reduction of TrkB protein levels in Act‐CreER TrkBflox/flox mice treated with tamoxifen was associated with reduced severity of behavioral seizures evoked by stimulation. Treatment with 1NMPP1 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.