Timothy syndrome (TS), a rare autosomal-dominant disorder, is characterized by presence of a heart arrhythmia (long QT syndrome), which causes the cardiac muscle to take longer than usual to recharge between beats and can result in sudden death. Now scientists at Columbia University have discovered that a common FDA-approved over-the counter cough suppressant, dextromethorphan, can shorten the prolonged QT intervals in both cellular and mouse models of TS. The cellular studies were done using patient-derived induced pluripotent stem cells (iPSCs). These findings were reported in the online February 17 edition of Nature Cardiovascular Research.
Speaking to BioWorld Science, lead author Masayuki Yazawa said that "CDK5 inhibitors have limited clinical potential in cardiac diseases due to the critical role played by the cyclin-dependent kinases (CDKs) in cell cycle regulation. There are also adverse effects, such as hepatotoxicity. We had to find alternatives."
Yazawa is an assistant professor of rehabilitation and regenerative medicine at Columbia University and a core faculty member of Columbia Stem Cell Initiative. Previously, Yazawa's group had identified that the increased activity of cyclin-dependent kinase 5 (CDK5) was involved in the cardiac pathophysiology of TS.
A systematic literature review revealed SIGMAR1 as a potential target. Interestingly, studies had shown that activation of SIGMAR1 suppressed CDK5 activity in rodent neurons. Yazawa added that the SIGMAR1 is also found to be implicated in cardioprotection, via various mechanisms, including reduction of Ca2+ leakage into the cytosol via modulating certain calcium channels.
Since Yazawa's team was looking for clinically relevant drugs with established safety and toxicity profiles, they found their answer in an FDA-approved cough suppressant, dextromethorphan, which is a SIGMAR1 agonist. The authors found that dextromethorphan treatment of cardiomyocytes derived from iPSCs of patients with TS soothed the cells' irregular rhythm. Yazawa adds that "dextromethorphan activates SIGMAR1 and the activated SIGMAR1 directly interacts with CDK5 to reduce CDK5 protein expression and activity in the cardiomyocytes."
Moreover, the authors saw that SIGMAR1 also directly interacts with the Cav1.2 channel in cardiomyocytes from patients with TS, which is modulated by dextromethorphan. This further helped in normalization of cardiomyocyte rhythm. In addition to its effects on the Cav1.2 channel, activation of SIGMAR1 by dextromethorphan also increased potassium currents in cardiomyocytes from patients with TS. According to Yazawa, "This probably contributed to the normalization of action potentials and restoration of ion homeostasis in the cardiomyocytes from patients with TS."
The authors confirmed the findings derived from the cardiomyocyte experiments in a mouse model of inherited cardiac arrhythmia that mimics the cardiac pathophysiology of TS. When tested in vivo, dextromethorphan also normalized the prolonged QT intervals in the mouse model. However, these studies were not done in a long QT syndrome model, due to non-availability of the same.
Yazawa cautions that it is still early to indicate whether dextromethorphan can be used to treat long QT patients. According to him, "the drug has a short half-life and would have to be used long term, as this is a chronic ailment, and its tolerability and long-term use is limited by its tendency to induce nausea." The authors, in their paper, also note that overdose of dextromethorphan could also potentially lead to severe adverse cardiac events and the pharmacological profile of dextromethorphan in infants and young children has not been fully investigated, which may comprise the main demographic of patients with TS.
While it is premature for dextromethorphan to be a viable clinical alternative in patients with long QT, the study "indicates that SIGMAR1 is a potential therapeutic target for long QT syndrome." Yazawa and his team are now focusing their efforts on understanding the other molecular players involved in SIGMAR1's role in modulating Ca2+ channels and ion homeostasis in cardiomyocytes. On the translational front, the group is looking at other SIGMAR1 agonists that can act as alternatives to dextromethorphan