Nova estratégia de proteção cognitiva para tratar a epilepsia pela prevenção do impacto da clivagem mediada por TrkB-FL

Our goal is to test the potential of preventing TrkB-FL cleavage and/or reducing TrkB-ICD levels as a therapeutic strategy to treat seizures and mitigate cognitive comorbidities. This scientific goal is grounded on the hypothesis that TrkB-FL cleavage has a role in epilepsy severity and cognitive comorbidities. To achieve this goal 4 specific objectives are planned: 1- Evaluate the impact of TrkB-ICD in epilepsy symptoms; 2- Develop a new compound to promote TrkB-ICD clearance; 3- Found small molecules to prevent TrkB-FL cleavage and 4- Promote epilepsy awareness, reduce stigma related to epilepsy and disseminate scientific results. Although there is a vast number of commercially available anti-seizure medications (ASM), more than 30% of patients present refractory epilepsy and most patients have relevant comorbidities such as memory impairments. The discovery of a new ASM with cognitive protection would have several beneficial outcomes, by improving treatment adherence, enhancing productivity, reducing healthcare costs, alleviating caregiver burdens, creating market opportunities, and stimulating further research and development investments in the field of epilepsy therapeutics. The involvement of BDNF signaling in epilepsy has been a conundrum. If on one hand the potentiation of signaling pathways mediated by BDNF can increase excitability (3), on the other it promotes important molecular mechanisms for neuroprotection and cognition (6). Indeed, there are studies pointing BDNF as a pro-epileptic and others as an anti-epileptic mediator (2,3). This apparent contradiction may be related to the incomplete knowledge of the molecular mechanisms involved in epilepsy. This project will provide novel therapeutic strategies with dual effects, ASM and cognitive protector, but will also provide important information about the role of BDNF mediated signaling in epilepsy and importantly will create awareness and reduce stigma related to epilepsy. This project will provide innovative therapeutic approaches, particularly centered on safeguarding cognitive capabilities, namely memory, signifying a revolutionary paradigm shift within the domain. Going beyond seizure management, these approaches strive to elevate the overall quality of life for those facing epilepsy. They inspire optimism for a future where both seizures and cognitive challenges are adeptly addressed, enabling patients to lead gratifying and cognitively robust lives. Importantly by targeting a novel therapeutic target, the solutions arising from this project will be particularly important to manage drug resistant epilepsy where the existing drugs failed. In conclusion, the short-term impact of our project lies in the knowledge gained with the first proof of concept studies based on a novel approach to treat and manage epilepsy treatment. This translational project holds considerable promise for future collaborations with pharmaceutical and biotech companies. Efforts will be dedicated to evaluating results patentability, ensuring their exploitability with the protection of the intellectual property rights (IPR) generated within the project. Looking ahead, the long-term ramifications of this endeavor could be substantial, both economically and socially, through the development of innovative therapies that significantly enhance the lives of individuals afflicted with epilepsy.