Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome

Abstract

Rett syndrome (RS) is a severe X-linked neurological disorder in which most patients have mutations in the methyl-CpG binding protein2 (MECP2) gene. No effective treatment exists. We previously showed that the Mecp2-deficient mice, a mouse model of RS, have highly variable respiratory rhythm and frequent apneas due to reduced norepinephrine (NE) content, and a drastic decrease of tyrosine hydroxylase (TH)-expressing neurons in the medulla. We showed here that treating these mice with desipramine (DMI), which specifically inhibits NE reuptake, significantly improved their respiratory rhythm during several weeks. In addition, the treatment significantly extended their lifespan. At the cellular level, we showed that the reduced number of TH-expressing neurons before treatment in the mutant animals was not due to apoptosis. Conversely, we found that DMI treatment increased the number of TH-expressing neurons in the mutant brainstem to reach wild-type levels. We showed that this increase was not due to cellular proliferation. We propose that the Mecp2-deficient TH-expressing neurons lose their ability to synthesize TH at some point during their postnatal development. Our results suggest that a pharmacological stimulation of the noradrenergic system could be a promising approach for the treatment of the respiratory dysfunction which causes a significant proportion of death in RS patients.

Effect of desipramine on patients with breathing disorders in RETT syndrome

“…When these mice were treated in vivo with desipramine (DMI), which specifically inhibits NA reuptake, the number of apneas was strongly reduced in comparison to the placebo group (−75% after 3 days of treatment). In addition, the treatment significantly extended their lifespan 12. This effect, observed with administration by intraperitoneal route was confirmed in another independent study giving DMI by oral route 13.…”

“…This effect, observed with administration by intraperitoneal route was confirmed in another independent study giving DMI by oral route 13. At cellular level, DMI maintained the number of TH‐expressing neurons in the brainstem of Mecp2‐deficient mice 12. On the basis of these preclinical data and the scientific literature showing that RTT patients also present a reduced amount of available NE in the CNS14, orphan designation was granted by the European Commission for the treatment of RTT with desipramine in 2011 15, 16.…”

Rett Syndrome: Reaching for Clinical Trials

“…As these monoamines are associated with the regulation of breathing patterns in the brainstem, augmenting their levels may be therapeutic for breathing dysfunction in RTT. Desipramine is an antidepressant that blocks the uptake of noradrenaline, and has been shown to reverse the breathing dysregulation in male Mecp2 knockout mice [101,102]. Desipramine is currently in a Phase II double-blind, placebo-controlled clinical trial for RTT.…”

Traitement pharmacologique dans le syndrome de Rett

“…Les souris Mecp2 -/y ont été traitées tous les jours par injection intrapéritonéale à partir de la période où apparaissaient des troubles respiratoires marqués (Figure 1). Les souris déficientes traitées par la désipramine présentent une amélioration notable du rythme respiratoire durant plusieurs semaines, maintenant le niveau d'apnée à un seuil très bas [8]. De manière encore plus intéressante, le traitement prolonge la durée de vie des souris déficientes d'environ 50 % par rapport aux souris non traitées, ou traitées par un placebo.…”