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Effect of a serotonin 1a agonist, dopamine D2‐like agonist/partial agonist on respiration in methyl‐CpG‐binding protein 2 (Mecp2) deficient mice
Author(s) -
Bissonnette John M,
Lioy Daniel T,
Knopp Sharon J
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1111.25
Subject(s) - agonist , medicine , rett syndrome , dopamine agonist , endocrinology , partial agonist , mecp2 , sleep apnea , serotonin , endogenous agonist , chemistry , pharmacology , receptor , dopamine receptor d1 , biochemistry , gene , phenotype
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 Mecp2 tm1−1Jae 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