Effect of Sarizotan, a 5-HT_1aand D2-Like Receptor Agonist, on Respiration in Three Mouse Models of Rett Syndrome

Abstract

Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist (R)-(+)-8-hydroxy-dipropyl-2-aminotetralin hydrobromide (8-OH-DPAT) significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist and a dopamine D2-like agonist/partial agonist, has been used in clinical trials for the treatment of l-dopa-induced dyskinesia. The purpose of this study was to evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Studies were performed in Bird and Jaenisch strains of methyl-CpG-binding protein 2--deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous female mice of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography, and locomotion was determined with open-field recording. Sarizotan or vehicle was administered 20 minutes before a 30-minute recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Sarizotan reduced the incidence of apnea in all three RTT mouse models to approximately 15% of their pretreatment levels. The irregular breathing pattern was corrected to that of wild-type littermates. When administered for 7 or 14 days, apnea decreased to 25 to 33% of the incidence seen with vehicle. This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT.

Reduced computational modelling of Kölliker‐Fuse contributions to breathing patterns in Rett syndrome

“…; Abdala et al . a , b ). Hence, we next explored the effects of simulated 5‐HT 1A agonist application in our models.…”

“…; Abdala et al . a , b ). We obtained these results using not just one but three related but distinct models, each of which makes distinct predictions about which key pathways and interactions allow these effects to emerge (Fig.…”

“…; Abdala et al . a , b ). To simulate the application of a 5‐HT 1A agonist, we strengthened inhibitory connections within the medullary kernel and we activated 5‐HT 1A ‐sensitive potassium channels in all populations (detailed in the equations below), based on previous modelling work (Shevtsova et al .…”

“…Finally, the models are used to explore a mechanistic rationale for experimental findings using 5‐HT 1A agonists to treat RTT respiratory dysfunction (Abdala et al . , a , b ). Based on these results, the models considered yield predictions related to the network dynamics underlying the emergence and potential suppression of RTT respiratory dysfunction, particularly spontaneous apnoeas.…”

Rett Syndrome: Reaching for Clinical Trials

“…The atypical tricyclic antidepressant tianeptine (REV-003) also improved respiratory activity in Mecp2-deficient mice, although this effect may reflect modulation of monoamine levels, glutamate receptor function, or BDNF levels [103]. Sarizotan and NLX-101 are selective agonists of the 5-HT1α receptor that significantly improved breathing patterns and reduced the frequency of apneas in Mecp2--deficient mice [104].…”