Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1

Autor: Volker Mall, Victor-Felix Mautner, Tobias Winkler, L Freudenberg, F Mainberger, Steffen Berweck, Florian Heinen, Karen Lidzba, Nikolai H. Jung, Susanne Langer, Ute Wahlländer, Sofia Granström, Andreas Straube, Martin Zenker
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Male
Neurology
Time Factors
medicine.medical_treatment
Long-Term Potentiation
RAS-pathway
Cohort Studies
Medizinische Fakultät
Attention
Cerebral Cortex
biology
Anticholesteremic Agents
General Medicine
Paired associative stimulation (PAS)
Transcranial Magnetic Stimulation
Female
Lovastatin
medicine.drug
Research Article
Adult
medicine.medical_specialty
Neurofibromatosis 1
Developmental disorder
Decision Making
Clinical Neurology
gamma-Aminobutyric acid
Synaptic plasticity
Young Adult
Transcranial magnetic stimulation (TMS)
Double-Blind Method
medicine
Humans
Neurochemistry
ddc:610
Long-term potentiation (LTP)
business.industry
Neural Inhibition
medicine.disease
Evoked Potentials
Motor
Neurofibromin 1
Transcranial magnetic stimulation
NF1
biology.protein
Neurology (clinical)
business
Neuroscience
Zdroj: BMC Neurology
ISSN: 1471-2377
Popis: Background Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders causing learning disabilities by mutations in the neurofibromin gene, an important inhibitor of the RAS pathway. In a mouse model of NF1, a loss of function mutation of the neurofibromin gene resulted in increased gamma aminobutyric acid (GABA)-mediated inhibition which led to decreased synaptic plasticity and deficits in attentional performance. Most importantly, these defictis were normalized by lovastatin. This placebo-controlled, double blind, randomized study aimed to investigate synaptic plasticity and cognition in humans with NF1 and tried to answer the question whether potential deficits may be rescued by lovastatin. Methods In NF1 patients (n = 11; 19–44 years) and healthy controls (HC; n = 11; 19–31 years) paired pulse transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (paired pulse) and synaptic plasticity (paired associative stimulation). On behavioural level the Test of Attentional Performance (TAP) was used. To study the effect of 200 mg lovastatin for 4 days on all these parameters, a placebo-controlled, double blind, randomized trial was performed. Results In patients with NF1, lovastatin revealed significant decrease of intracortical inhibition, significant increase of synaptic plasticity as well as significant increase of phasic alertness. Compared to HC, patients with NF1 exposed increased intracortical inhibition, impaired synaptic plasticity and deficits in phasic alertness. Conclusions This study demonstrates, for the first time, a link between a pathological RAS pathway activity, intracortical inhibition and impaired synaptic plasticity and its rescue by lovastatin in humans. Our findings revealed mechanisms of attention disorders in humans with NF1 and support the idea of a potential clinical benefit of lovastatin as a therapeutic option.
Databáze: OpenAIRE
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