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1.
Cell Mol Life Sci ; 81(1): 215, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38739166

RESUMEN

Down syndrome (DS) is a genetic disease characterized by a supernumerary chromosome 21. Intellectual deficiency (ID) is one of the most prominent features of DS. Central nervous system defects lead to learning disabilities, motor and language delays, and memory impairments. At present, a prenatal treatment for the ID in DS is lacking. Subcutaneous administration of synthetic preimplantation factor (sPIF, a peptide with a range of biological functions) in a model of severe brain damage has shown neuroprotective and anti-inflammatory properties by directly targeting neurons and microglia. Here, we evaluated the effect of PIF administration during gestation and until weaning on Dp(16)1Yey mice (a mouse model of DS). Possible effects at the juvenile stage were assessed using behavioral tests and molecular and histological analyses of the brain. To test the influence of perinatal sPIF treatment at the adult stage, hippocampus-dependent memory was evaluated on postnatal day 90. Dp(16)1Yey pups showed significant behavioral impairment, with impaired neurogenesis, microglial cell activation and a low microglial cell count, and the deregulated expression of genes linked to neuroinflammation and cell cycle regulation. Treatment with sPIF restored early postnatal hippocampal neurogenesis, with beneficial effects on astrocytes, microglia, inflammation, and cell cycle markers. Moreover, treatment with sPIF restored the level of DYRK1A, a protein that is involved in cognitive impairments in DS. In line with the beneficial effects on neurogenesis, perinatal treatment with sPIF was associated with an improvement in working memory in adult Dp(16)1Yey mice. Perinatal treatment with sPIF might be an option for mitigating cognitive impairments in people with DS.


Asunto(s)
Modelos Animales de Enfermedad , Síndrome de Down , Neurogénesis , Animales , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/patología , Síndrome de Down/metabolismo , Síndrome de Down/complicaciones , Síndrome de Down/genética , Neurogénesis/efectos de los fármacos , Ratones , Femenino , Embarazo , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/efectos de los fármacos , Microglía/metabolismo , Microglía/efectos de los fármacos , Microglía/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas/genética , Quinasas DyrK , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Masculino , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/patología
2.
Am J Respir Crit Care Med ; 204(10): 1200-1210, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34478357

RESUMEN

Rationale: Congenital central hypoventilation syndrome (CCHS) is characterized by life-threatening sleep hypoventilation and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome. Objectives: To determine if Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms. Methods: Apneas were classified as central, obstructive, or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparations. Measurements and Main Results: The median (interquartile range) of obstructive apnea frequency was 2.3 (1.5-3.3)/min in Phox2b27Ala/+ pups versus 0.6 (0.4-1.0)/min in wild types (P < 0.0001). Obstructive apnea duration was 2.7 seconds (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7 seconds (1.1-1.9) in wild types (P < 0.0001). Central and mixed apneas presented similar significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared with wild-type preparations. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal activity with respect to phrenic activity onset (P < 0.001). Conclusions: The Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely because of hypoglossal dysgenesis. These results thus demand attention toward obstructive events in infants with CCHS.


Asunto(s)
Hipoventilación/congénito , Hipoventilación/diagnóstico , Hipoventilación/genética , Hipoventilación/fisiopatología , Apnea Central del Sueño/congénito , Apnea Central del Sueño/diagnóstico , Apnea Central del Sueño/genética , Apnea Central del Sueño/fisiopatología , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Proteínas de Homeodominio/genética , Humanos , Ratones , Mutación , Factores de Transcripción/genética
3.
J Sleep Res ; 30(5): e13337, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33880823

RESUMEN

A combination of noradrenergic and antimuscarinic agents reduces the apnea-hypopnea index (AHI) in adult patients with obstructive sleep apnoea (OSA) via reduced upper airway collapsibility, suggesting that a shift in the sympathovagal balance improves OSA. The objectives of our present case-control study were to assess heart rate variability (HRV) indices in the stages of sleep in children with and without OSA to evaluate OSA-induced sleep HRV modifications and to assess whether increased collapsibility measured during wakefulness is associated with reduced sympathetic activity during non-rapid eye movement (NREM) sleep. Three groups of 15 children were matched by sex, age, z-score of body mass index and ethnicity: non-OSA (obstructive AHI [OAHI] <2 events/hr), mild (OAHI ≥2 to <5 events/hr) or moderate-severe (OAHI ≥5 events/hr) OSA. Pharyngeal compliance was measured during wakefulness using acoustic pharyngometry. HRV indices (time and frequency domain variables) were calculated on 5-min electrocardiography recordings from polysomnography during wakefulness, NREM and REM sleep in periods free of any event. As compared to children without OSA, those with OSA (n = 30) were characterised by increased compliance and no physiological parasympathetic tone increase in REM sleep. Children with increased pharyngeal compliance (n = 21) had a higher OAHI due to higher AHI in NREM sleep, whereas their sympathetic tone was lower than that of those with normal compliance (n = 24). In conclusion, children with increased pharyngeal compliance exhibit decreased sympathetic tone associated with increased AHI in NREM sleep. Therapeutics directed at sympathovagal balance modifications should be tested in childhood OSA.


Asunto(s)
Apnea Obstructiva del Sueño , Estudios de Casos y Controles , Estudios Transversales , Frecuencia Cardíaca , Humanos , Polisomnografía
4.
Arch Pediatr ; 31(3): 205-208, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38538464

RESUMEN

Congenital central hypoventilation syndrome (CCHS) is an autosomal dominant disease that is caused by heterozygous mutations in the paired-like homeobox 2B gene (PHOX2B). Madani et al. described an abnormally high degree of not only central apnea but also obstructive and mixed apnea in Phox2b27Ala/+newborn mice. Newborns with CCHS must undergo polysomnography for obstructive respiratory events in order to guide the optimal ventilation strategy if oxygen desaturation, bradycardia, and malaise persist under noninvasive ventilation. Newborns and infants with CCHS must be systematically tested for obstructive apnea, especially in cases of inefficient noninvasive ventilation.


Asunto(s)
Obstrucción de las Vías Aéreas , Hipoventilación , Apnea Central del Sueño , Apnea Obstructiva del Sueño , Animales , Niño , Humanos , Lactante , Recién Nacido , Ratones , Obstrucción de las Vías Aéreas/etiología , Proteínas de Homeodominio/genética , Hipoventilación/congénito , Mutación , Apnea Central del Sueño/diagnóstico , Apnea Central del Sueño/genética , Apnea Central del Sueño/terapia , Factores de Transcripción/genética
5.
Mol Ther Nucleic Acids ; 35(4): 102319, 2024 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-39329148

RESUMEN

Congenital central hypoventilation syndrome (CCHS), a rare genetic disease caused by heterozygous PHOX2B mutations, is characterized by life-threatening breathing deficiencies. PHOX2B is a transcription factor required for the specification of the autonomic nervous system, which contains, in particular, brainstem respiratory centers. In CCHS, PHOX2B mutations lead to cytoplasmic PHOX2B protein aggregations, thus compromising its transcriptional capability. Currently, the only available treatment for CCHS is assisted mechanical ventilation. Therefore, identifying molecules with alleviating effects on CCHS-related breathing impairments is of primary importance. A transcriptomic analysis of cells transfected with different PHOX2B constructs was used to identify compounds of interest with the CMap tool. Using fluorescence microscopy and luciferase assay, the selected molecules were further tested in vitro for their ability to restore the nuclear location and function of PHOX2B. Finally, an electrophysiological approach was used to investigate ex vivo the effects of the most promising molecule on respiratory activities of PHOX2B-mutant mouse isolated brainstem. The histone deacetylase inhibitor SAHA was found to have low toxicity in vitro, to restore the proper location and function of PHOX2B protein, and to improve respiratory rhythm-related parameters ex vivo. Thus, our results identify SAHA as a promising agent to treat CCHS-associated breathing deficiencies.

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