A293 SQUALAMINE INCREASES VAGAL AFFERENT FIRING FREQUENCY IN AGING MICE
Notice bibliographique
Résumé
A large portion of the aging population exhibit comorbid gastrointestinal (GI) disorders and common age-related neurodegenerative conditions often including constipation, sleep disturbance, and depression. Luminal gut contents and microbiota have the ability to influence mood and behaviour through the vagal gut-brain axis. Squalamine, an aminosterol originally isolated from the dogfish shark, is a potent stimulator of the enteric nervous system and is currently in a Phase 2a study to evaluate its effect on constipation and other non-motor symptoms of Parkinson’s disease. We have recently shown that constipation in aged mice could be reversed by squalamine acting on the enteric nervous system. The purpose of this study is to explore the impact of aging on vagal afferent signaling in mice and evaluates the effects of squalamine on vagal outflow in this model. We hypothesize that squalamine will increase vagal afferent firing frequency in aged mice. Jejunal segments with attached mesentery from old (18–24 months) and young (3 months) male CD1 mice were excised, pinned out in a petri dish of Krebs and dissected to isolate the mesenteric nerve bundle. The jejunum was cannulated at both ends and luminally perfused with Krebs solution or Krebs with added squalamine (10µM). The mesenteric nerve bundle was sucked onto with a glass micropipette attached to a patch-clamp electrode and multi-unit electrical activity was recorded using an amplifier and signal converter. Single-unit firing was isolated using Dataview software and vagal fibres were identified by response to CCK. Basal afferent vagal firing frequency was measured in old and young mice before and after treatment with squalamine. Mean basal vagal afferent firing frequency was 0.58 ± 0.13 Hz (N=30[4]) in old mice compared to 1.1 ± 0.11 Hz (N=45[3]) for young mice representing a 57% reduction (p = 0.0016) in firing frequency in the elderly animals compared with the younger controls. Luminal application of squalamine increased vagal afferent firing frequency by 43% to 1 ± 0.097 Hz (p < 0.0001) in old mice compared to an increase of 28% to 1.4 ± 0.11 Hz (p = 0.001) in young mice. The onset latency to the peak of the squalamine response was 15 to 20 min. The results demonstrate that luminal exposure to squalamine: (1) stimulates vagal afferent signaling in both young and old mice, (2) the magnitude of the effect is larger in the older animals. The data suggest that diminished vagal afferent firing with aging is at least partially reversible with luminally-administered squalamine. NRC
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».