DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Re-Imagining Epilepsy Treatments – A Cocktail of Novel Small Molecules Shows Promise for Blocking Post-Traumatic Epilepsy

Posted July 30, 2021

Dr. Jeanne Paz, Gladstone Institutes

Dr. Jeanne Paz, Gladstone Institutes
Dr. Jeanne Paz

Traumatic brain injury (TBI) can lead to reoccurring seizures, a condition known as post-traumatic epilepsy (PTE). The thalamus, a deep subcortical structure of the brain, is likely involved in development of PTE. The time course by which thalamic damage can putatively trigger seizures can evolve over the course of months or even years after the injury. This protracted time course of brain cell loss and damage to blood vessels in the brain and within the thalamus may provide a critical intervention window to prevent seizures from becoming PTE.

Dr. Jeanne Paz, an associate investigator at Gladstone Institutes, uses high tech electrophysiology approaches and optogenetics to further our understanding of PTE to improve future outcomes for patients. Funded by a Fiscal Year 2015 (FY15) Epilepsy Research Program (ERP) Idea Development Award, her lab is researching the role of abnormal plasticity in cortico-thalamo-cortical (CTC) circuits after TBI and how it may lead to subsequent PTE. Dr. Paz has identified a molecular target, C1q, that is a synaptic plasticity inhibitor as a potential target for future treatments of PTE. Based on her experiments in animals, she posits that even the mildest TBIs may benefit from C1q inhibition treatments. In addition to blocking injury-related plasticity, C1q treatment also seems to alleviate some of the neuroinflammation seen with these injuries.  

While C1q has shown promise to reduce neuroinflammation and prevented the development of epileptic spikes, it has not shown the ability to block all epilepsy-related brain activity. Dr. Paz is now investigating a variety of strategies that may work in conjunction with C1q to completely stop seizure activity in these early studies. She is examining whether biochemical alterations to the brain in conjunction with C1q treatment may work, as well as whether other small molecules that focus on other aspects of post-TBI damage can complement the activity of C1q. Specifically, she received a FY19 ERP Idea Development Award to study two new molecules: RA8 and SM2. These small molecules might be able to reduce astrogliosis and thalamic neurodegeneration induced by TBI. Dr. Paz’s systematic approach may one day lead to a cocktail of inhibitors that block seizures from becoming PTE.

Links:

Public and Technical Abstracts:  Deconstruction and Control of Neural Circuits in Post-Traumatic Epilepsy

Public and Technical Abstracts:  Developing Small Molecule Therapeutics for Preventing Post-Traumatic Epilepsy

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Last updated Friday, July 30, 2021