Long-term effects of pharmacological inhibition of anaplastic lymphoma kinase in neurofibromatosis 1 mutant mice

Destine Krenik, Joseph B. Weiss, Jacob Raber

Research output: Contribution to journalArticlepeer-review

Abstract

Neurofibromatosis type 1 (NF1) is associated with behavioral alterations and cognitive impairments. There is a genetic interaction between NF1 and the receptor tyrosine kinase Alk. Short-term pharmacological Alk inhibition, with a compound FDA-approved for cancer starting 10 days prior to cognitive testing, was shown to improve cognitive performance of NF1 heterozygous (HET) mice. However, effects of long-term Alk inhibition on behavioral cognitive performance are not known. Therefore, in the study described below we determine the effects of prolonged pharmacological Alk inhibition for 24 weeks on behavioral and cognitive performance of NF1 HET mice. As these studies have the ultimate objective of developing a treatment for humans with neurofibromatosis and acceptable side effects in the context of cancer are not acceptable in the context of long-term treatment of patients with neurofibromatosis, we included additional behavioral tests of anxiety-like and depressive-like behaviors as well. Long-term effects of Alk inhibition had genotype-dependent effects, consistent with a specific interaction between Alk and NF1. Beneficial effects of long-term Alk inhibition in NF1 HET mice included rescue of impairments in object recognition in NF1 HET males and females, and improved cognitive performance of NF1 HET males and females in the water maze test. In contrast, long-term Alk inhibition had detrimental effects in WT mice not seen after short-term treatments. As longer treatments are translationally more relevant for NF1 patients, these data highlight the important to assess long-term effects of drugs, especially of repurposed drugs used originally as part of cancer therapy.

Original languageEnglish (US)
Article number113767
JournalBehavioural Brain Research
Volume423
DOIs
StatePublished - Apr 9 2022
Externally publishedYes

Keywords

  • Alk inhibition
  • Anxiety-like behavior
  • Depression-like behavior
  • Mice
  • NF1
  • Object recognition
  • Water maze

ASJC Scopus subject areas

  • Behavioral Neuroscience

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