A newly published paper in the Journal of Clinical Investigation examines the impact of the medicine propranolol in zebrafish and mouse models of cerebral cavernous malformation.
In explaining the relevance of the study, Dr. Issam Awad, the study’s co-PI states, “Propranolol, a widely used blood pressure and migraine medication, had long been known to be effective in pediatric cutaneo-skeletal venous hemangiomas. The mechanistic effect of propranolol had never been investigated in cerebrovascular malformations, including cavernous malformations (CA). Here, teams from Chicago, Duke, UCSD, and the Barrow Neurological Institute collaborated to show a compelling effect on CA.”
The team was able to demonstrate that propranolol is effective in inhibiting the development of large cavernous malformations. Mice treated with propranolol developed fewer lesions and the lesions that did form were smaller. There was no impact on bleeding detected by this study. Because of the mouse models used, the study was not designed to detect whether the medicine impacted the progression of existing lesions.
The caveat for this work is that the dosage of propranolol required to show this effect was higher than can be tolerated in humans. The plan moving forward is to test another beta-blocker, metoprolol, in mouse models. Metoprolol (brand names Toprol and Lopressor) acts in the same manner as propranolol but is better tolerated.
Dr. Awad shares a more technical explanation, “While the mechanism on venous hemangiomas is mediated by the propranolol R(+) enantiomer causing SOX18 inhibition rather than β1 receptor antagonism, the effect of propranolol on CA is conversely mediated via β1 adrenergic receptor antagonism, through the S(-) enantiomer, an effect also mimicked by the much better tolerated β1 antagonist metoprolol. In mouse models, propranolol primarily inhibited the development of large CAs, and did not impact bleeding. These results will compel clinical trials of propranolol or even the better-tolerated metoprolol in CAs.”
A small Phase 2 clinical trial of propranolol is currently underway in Italy. Results from this trial should become available in early 2022.
