Treatment with desipramine improves breathing and survival in a mouse model for Rett syndrome.
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.
Roux
Jean-Christophe
JC
INSERM, U491, Faculté de Médecine de La Timone, Marseille, F-13385, France. jean-christophe.roux@medecine.univ-cnrs.fr
Dura
Emmanuelle
E
Moncla
Anne
A
Mancini
Josette
J
Villard
Laurent
L
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D003891:Desipramine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D012119:Respiration / Q000187:drug effects*; D015518:Rett Syndrome / Q000188:drug therapy*; D015996:Survival Rate
D018759:Adrenergic Uptake Inhibitors; D051783:Methyl-CpG-Binding Protein 2; D003891:Desipramine; D009638:Norepinephrine