Repurposing a panel of Late Sodium Current Blockers for pharmacological targeting of Familial hemiplegic migraine 3: a dual-approach ex vivo study.

Familial hemiplegic migraine type 3 (FHM3) is a severe type of migraine that includes temporary weakness on one side of the body. It's caused by genetic changes in the protein, Nav1.1, which is crucial for sending electrical signals in the brain. Here at the CNR in Genoa, we have been studying this disease for several years to unravel its molecular pathogenic pathway. Our project aims to learn more about how FHM3 works, by examining its mechanisms at a level beyond individual brain cells, but still simpler than studying the whole brain. We will use neuronal cultures derived from the cortex of mice genetically modified with a FHM3-causing mutation. These cultures will mature, developing into a functional network. where the transmission of electrical signals via axons and synapses between cells is facilitated. We will study the spontaneous electrical activity of neuronal networks, observing the differences between cultures from heterozygous FHM3 and wild-type mice. Interestingly, we will also record the activity in FHM3 KI mouse brain slices. These slices preserve native circuitry and have indeed proven optimal in identifying pathophysiological mechanisms in models of neurodevelopmental and neurodegenerative diseases. Once our models are validated, we will test the effectiveness of compounds with potential therapeutic effects, such as GS967 or ranolazine that act on Nav1.1 current. Overall, we expect to find compounds worthy of further pharmacological studies. Importantly, since FHM3 and common migraines share several pathogenic mechanisms, the findings from the FHM3 research could be beneficial for common migraine patients.