Effect of a serotonin 1a agonist, dopamine D2‐like agonist/partial agonist on respiration in methyl‐CpG‐binding protein 2 (Mecp2) deficient mice

Abstract

We have recently shown that the serotonin 1a agonist, 8-OH-DPAT, markedly improves the incidence of apnea and restores regular breathing in Mecp2 deficient mice, models of Rett syndrome (Abdala et al PNAS, 2010). 8-OH-DPAT, however, is not a clinical available compound. Sarizotan (EMD 128130; (R)(_)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane hydrochloride), a full serotonin 1a agonist with agonist and partial agonist effects on dopamine D2-like receptor subtypes, has been used in Phase II trials to treat levodopa-induced dyskinesia. Studies were carried out in Mecp2tm1−1Jae heterozygous Mecp2 deficient female (Mecp2−/+) and wild type (WT) mice, 6.7 to 12.3 months old. Compared to WT, Mecp2−/+ mice breathed slower (143±11 vs 207±16 bpm), more irregular (irregularity score 0.29±0.03 vs 0.17±0.02) and had more apneas (148±7.2 vs 2.2±0.9/hr). Sarizotan, a generous gift from Gerd Bartoszyk, Merck KGaA, Darmstadt, effectively reduced the incidence of apnea in a dose dependant manner. At 5.0 mg/Kg ip apneas declined to 26.5±10.7 and irregularity to 0.16±0.03. Sarizotan is a promising drug for respiratory disorders in Rett syndrome. International Rett Syndrome Foundation; Northwest Rett Syndrome Foundation