Effects of Solid Lipid Curcumin Particle (Slcp) on Mtor Signaling in Vivo – Searching for a Mechanism-Based Therapeutic Strategy for Epilepsy in Tuberous Sclerosis Complex (Tsc)(3/3)

Epilepsy affects around 50 million people globally, with one-third developing drug-resistant epilepsy. One promising approach in treating epilepsy, antiepileptogenesis, has emerged recently. The mTOR signaling has been implicated in epileptogenesis due to several identified genetic epilepsies caused by gene mutations in mTOR pathway such as tuberous sclerosis complex (TSC). Nearly 90% of TSC patients has a history of epilepsy, with 60% of the epileptic patients develop refractory epilepsy. Thus, mTORinhibitors (sirolimus and its analog, everolimus) have been suggested to be used as a mechanism-based therapy to prevent epileptogenesis in TSC, and possibly other types of mTOR-associated epilepsies. Despite everolimus has been approved for treating seizures in TSC patients, its toxicity for long-term administration and the pharmacological effects on the growth and early development of infants are major concerns in treating TSC. Moreover, only 40% of TSC patients with refractory epilepsy show clinical responses to everolimus. Therefore, an alternative safe, effective mTOR inhibition treatment is required for treating epilepsy in TSC patients. We previously revealed that oral administration with a novel lapidated formulation of curcumin, solid lipid curcumin particle (SLCP), can inhibit mTOR activity and reverse neuropathological abnormalities in animal model. In this project, we further investigate how mTOR hyperactivation influences epilepsy development in the TSC mouse model, and explore whether
SLCP can mitigate epilepsy in this model.

We successfully generated the inducible neuron-specific Tsc1 knockout mouse model (Tsc1CKO), which develops spontaneous recurrent seizures after induction of Tsc1 gene knockout. Our results indicate that although there was no significant difference in the seizure onset time between the Tsc1CKO mice and the treated-group, the survival time was significantly extended after the SLCP treatment, suggesting that SLCP treatment may have some effects on ameliorating the epileptogenesis or the severity of epileptic behavior in Tsc1CKO mice. Furthermore, from the histological analyses in the brain tissues, we found that the mTOR activity was substantially augmented, and the cortical neurons were enlarged in Tsc1CKO mice, when compared to the wildtype mice. However, we found that the SLCP treatment did not alleviate these pathological changes, indicating that the SLCP treatment may exert its effects through a different mechanistic pathway instead of the presumable mTOR pathway. We also further conduct multiomics analyses, including metabolomics of the cerebral cortex and hippocampus, as well as RNA sequencing, aiming to clarify the metabolic abnormalities and gene changes caused by Tsc1 gene deletion, which will serve as a direction for future investigations. Although our pilot clinical trial could not be successfully completed for certain reasons, the collected data still indicates that SLCP may have potential therapeutic or ameliorative effects on epilepsy in patients with tuberous sclerosis. In the future, we will also work on improving the relevant trial procedures in order to conduct new related clinical trials.