Our work is inspired by the fact that current therapies focus on reducing seizures but are not aimed to cure epilepsy. Uncovering the mechanisms underlying epileptogenesis will allow us to effectively target root causes of epilepsy to prevent its progression. Our research has uncovered mechanistic evidence supporting the hypothesis that calpain overactivation is a key mechanism driving epileptogenesis. We have shown that there is a good correlation between calpain activity and seizure occurrence during early epileptogenesis. Also, calpain reactivation by spontaneous seizures might contribute to long-term occurrence of spontaneous seizures. Moreover, inhibition of calpain activation following status epilepticus (SE) ameliorates seizure burden, providing support for the idea that calpain dysregulation plays a role in epileptogenesis. Altogether, our research supports that calpain blockade ameliorates epilepsy progression.
Epileptogenesis Lab
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Principal InvestigatorMarco González, Ph.D.
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Our Research Goals
The team studies cellular mechanisms behind epilepsy to identify drug targets to prevent seizures. Their research has identified calpain overactivation as a key driver of epileptogenesis, and we are investigating blocking it as a potential drug target.
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Current Projects
A reduction in GABAergic drive precedes appearance of spontaneous seizures. We have found that proteins located at GABAergic synapses like gephyrin, the vesicular GABA transporter (VGAT) and the potassium chloride cotransporter (KCC2) undergo calpain-dependent cleavage during epileptogenesis. A time-dependent generation of break down products (BDPs) of these proteins was observed after pilocarpine-induced SE. Generation of these BDPs was partially blocked by a calpain inhibitor. This suggests that calpain-dependent loss of GABAergic proteins might promote the erosion of inhibitory drive contributing to hyperexcitability.
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Our Team
- Gelareh Vakilzadeh, Post-Doc
- Daniel Fonseca-Barriendos, Post-Doc
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