piperidines and Neurofibromatosis-1

Cases of neurofibromatosis type 1 (

Topics: Adolescent; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Germ-Line Mutation; Homozygote; Humans; Male; Neurofibromatosis 1; Neurofibromin 1; Piperidines; Proto-Oncogene Proteins c-ret; Quinazolines; Thyroid Neoplasms; Treatment Outcome

Neurofibromatosis type 1 (NF1), a genetically determined neurodevelopmental disorder and tumor syndrome, is associated with cognitive impairments, including in executive function and sleep-related problems. Consistent with the human data, NF1 heterozygous (Het) mice show impaired spatial learning and memory in the water maze and extinction of contextual fear memory. It is not clear whether neurological phenotypes might depend on the parental carrier. In this study, we compared the behavioral and cognitive performance of NF1 Het and wild-type litter mates with either the father (PC) or the mother (MC) as the NF1 carrier on a F1 C57BL/66/129SvJ background. The behavioral and cognitive phenotypes and responsiveness to Alk inhibition in heterozygous NF1 offspring depended on whether the parental carrier was maternal or paternal. Alk inhibition (20 mg/kg) increased activity levels during the dark period in NF1 Het PC, but not MC, mice. In the water maze, NF1 Het PC, but not MC, mice showed reduced cognitive flexibility and impaired ability to locate the third hidden platform location, which was improved by Alk inhibition (3.6 mg/kg). Consistent with reduced cognitive flexibility, WT, but not NF1, mice showed better performance in the third than second water maze probe trial. Finally, Alk inhibition (10 mg/kg) increased baseline activity of NF1 MC, but not PC, mice during the fear conditioning test. Thus, the effective dose depends on the behavioral test and genotype but indicates that in NF1 patients cognitive flexibility might be particularly sensitive to Alk inhibition.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Behavior, Animal; Carbazoles; Cognition; Cognitive Dysfunction; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fear; Female; Genotype; Heterozygote; Male; Maze Learning; Mice; Mice, Inbred C57BL; Neurofibromatosis 1; Neurofibromin 1; Parents; Piperidines

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Female; Fibroma; Humans; Middle Aged; Neurofibromatosis 1; Piperidines; Pyrimidines; Pyrroles; Skin Neoplasms

Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations are found in 90% of patients with neurofibromatosis, a syndrome associated with disabling cognitive impairment. Drosophila studies have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 in cognitive performance. In addition, pharmacologic inhibition of Alk improves cognitive performance in heterozygous NF1 mutant flies. In this study, we tested whether pharmacological inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments. Cognitive impairment of spatial memory retention observed in heterozygous NF1 mutant mice was rescued by the Alk inhibitor. These data support the hypothesis that inhibition of Alk may cognitively benefit patients with Neurofibromatosis 1.

Topics: Anaplastic Lymphoma Kinase; Animals; Carbazoles; Cognitive Dysfunction; Disease Models, Animal; Female; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Mice, Knockout; Neurofibromatosis 1; Nootropic Agents; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Spatial Memory; Swimming

Topics: Administration, Intravenous; Adult; Analgesia, Obstetrical; Analgesia, Patient-Controlled; Factor V; Female; Humans; Infant, Newborn; Neurofibroma; Neurofibromatosis 1; Pain Management; Pain Measurement; Piperidines; Remifentanil; Spain; Visual Analog Scale

Topics: Adult; Androstanes; Apnea; Humans; Male; Neurofibromatosis 1; Neuromuscular Nondepolarizing Agents; Piperidines; Succinylcholine