Protective role of mirtazapine in adult female Mecp2+/− mice and patients with Rett syndrome

Autor: Claudio De Felice, Enrico Tongiorgi, Silvia Leoncini, Cinzia Signorini, Javier Flores Gutiérrez, Giulia Natali, Joussef Hayek
Přispěvatelé: Flores Gutierrez, J., De Felice, C., Natali, G., Leoncini, S., Signorini, C., Hayek, J., Tongiorgi, E.
Rok vydání: 2020
Předmět:
Methyl-CpG-Binding Protein 2
Antidepressant
Irritability/aggressiveness
Mice
Rett syndrome
0302 clinical medicine
Retrospective Studie
Medicine
0303 health sciences
Parvalbumin neuron
Intellectual disability disorder
Antidepressants
medicine.anatomical_structure
Female
Parvalbumin neurons
Primary motor cortex
Motor learning
Human
Motor cortex
medicine.drug
Motor learning deficit
medicine.medical_specialty
Cognitive Neuroscience
Mirtazapine
Intellectual disability disorders
lcsh:RC321-571
Pathology and Forensic Medicine
MECP2
03 medical and health sciences
Internal medicine
Motor learning deficits
Somatosensory cortex
Animals
Disease Models
Animal
Humans
Retrospective Studies
Rett Syndrome
lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
030304 developmental biology
Animal
business.industry
Research
medicine.disease
Endocrinology
Mood disorders
Irritability/aggressivene
Disease Models
Pediatrics
Perinatology and Child Health
Neurology (clinical)
business
030217 neurology & neurosurgery
Zdroj: Journal of Neurodevelopmental Disorders
Journal of Neurodevelopmental Disorders, Vol 12, Iss 1, Pp 1-20 (2020)
ISSN: 1866-1955
1866-1947
DOI: 10.1186/s11689-020-09328-z
Popis: Background Rett syndrome (RTT), an X-linked neurodevelopmental rare disease mainly caused by MECP2-gene mutations, is a prototypic intellectual disability disorder. Reversibility of RTT-like phenotypes in an adult mouse model lacking the Mecp2-gene has given hope of treating the disease at any age. However, adult RTT patients still urge for new treatments. Given the relationship between RTT and monoamine deficiency, we investigated mirtazapine (MTZ), a noradrenergic and specific-serotonergic antidepressant, as a potential treatment. Methods Adult heterozygous-Mecp2 (HET) female mice (6-months old) were treated for 30 days with 10 mg/kg MTZ and assessed for general health, motor skills, motor learning, and anxiety. Motor cortex, somatosensory cortex, and amygdala were analyzed for parvalbumin expression. Eighty RTT adult female patients harboring a pathogenic MECP2 mutation were randomly assigned to treatment to MTZ for insomnia and mood disorders (mean age = 23.1 ± 7.5 years, range = 16–47 years; mean MTZ-treatment duration = 1.64 ± 1.0 years, range = 0.08–5.0 years). Rett clinical severity scale (RCSS) and motor behavior assessment scale (MBAS) were retrospectively analyzed. Results In HET mice, MTZ preserved motor learning from deterioration and normalized parvalbumin levels in the primary motor cortex. Moreover, MTZ rescued the aberrant open-arm preference behavior observed in HET mice in the elevated plus-maze (EPM) and normalized parvalbumin expression in the barrel cortex. Since whisker clipping also abolished the EPM-related phenotype, we propose it is due to sensory hypersensitivity. In patients, MTZ slowed disease progression or induced significant improvements for 10/16 MBAS-items of the M1 social behavior area: 4/7 items of the M2 oro-facial/respiratory area and 8/14 items of the M3 motor/physical signs area. Conclusions This study provides the first evidence that long-term treatment of adult female heterozygous Mecp2tm1.1Bird mice and adult Rett patients with the antidepressant mirtazapine is well tolerated and that it protects from disease progression and improves motor, sensory, and behavioral symptoms.
Databáze: OpenAIRE
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