Oxidative stress and Cerebral Cavernous Malformations (CCM): from disease mechanisms toward prevention and treatment

Cerebral Cavernous Malformations (CCM) is a major cerebrovascular disease affecting 0.1-0.5% of the world's population. It is characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits and fatal intracerebral hemorrhage. To date there are not direct therapeutic approaches for CCM disease, besides the surgical removal of accessible lesions in patients with recurrent hemorrhage or intractable seizures. The characterization of the molecular mechanisms underlying the CCM disease should provide fundamental insights into the development of novel, safe and effective therapeutic strategies. Previously, we found that KRIT1 (CCM1), a gene responsible for CCM, is involved in the maintenance of the intracellular reactive oxygen species (ROS) homeostasis to prevent oxidative cellular damage, raising the possibility that CCM lesions may result from an impaired endothelial cell defense against oxidative stress, and opening new therapeutic perspectives. In this light, we tested the effectiveness of distinct antioxidant compounds in cellular models of CCM disease. Among others, we found that plant secondary metabolites of the oat avenanthramide family, including N-(E)-p-coumaroyl-3-hydroxyanthranilic acid (yeast avenanthramide, YAv), a novel phenolic compound produced by genetically engineered yeast and endowed with excellent antioxidant properties, were effective in rescuing molecular phenotypes associated with KRIT1 loss-of-function, suggesting potential therapeutic benefits for CCM disease.