A New Molecular Mechanism Underlying Epileptogenesis, and a Novel Therapeutic Strategy for Treating Epilepsy

Abstract

Epilepsy is the fourth most prevalent neurological disorder and starts with an abnormal hyper-synchronized neuronal discharge, i.e., a seizure. A status epilepticus (SE) or any brain injury (genetic or acquired) could cause the initial seizure. After the initial seizure, ill-defined molecular and neuronal remodeling occurs in a process called epileptogenesis and results in spontaneous recurrent seizures (SRS). Elaborating the critical molecular mechanisms of epileptogenesis is central to understand the establishment of chronic seizures and paves the way for new therapeutic interventions.

In Chapter 2, I investigated the molecular and metabolic mechanisms following SE using pilocarpine and kainate mouse models to induce SE as a model of Temporal lobe epilepsy (TLE), one of the most common types of epilepsy in adults, and epileptogenesis. Biochemistry, metabolomics, and confocal microscopy results identified a transient induction of Wnt signaling at day five following SE in both models. The aberrant Wnt activation drove a metabolic reprogramming and activation of the mTOR pathway in the hippocampus of epilepsy mouse. Both Wnt and mTOR pathways contribute to chronic seizures and are associated with a Warburg effect, a metabolic reprogramming seen in cancer cells. We elaborated a Warburg-like aerobic metabolism that was split between neurons and astrocytes. This novel split Warburg-like metabolism inhibited AMPK activity and triggered activation of the downstream mTOR pathway. We tested our mechanistic model with a glycolytic inhibitor, 2-deoxyglucose, and showed both re-activation of AMPK and a reversal of mTOR activation, but no effect on upstream Wnt signaling. Consistent with an epileptogenic hippocampus, GABA levels were decreased. These detailed mechanistic studies unveil events that feed into the iconic mTOR activation of epileptogenesis, by elaborating a new pathway from Wnt signaling triggering a novel Warburg metabolic rearrangement—both of which lie upstream of mTOR activation. The definition of a new mechanism provides the basis for discovering new insights into potential disease-modifying therapeutic strategies to be applied in epileptogenesis.

In fact, the studies in Chapter 2 define a platform for discovering new therapeutic agents. Chapter 3 demonstrated the efficacy of a new compound combination defined as CHA1, which is an agent that suppresses Wnt signaling during epileptogenesis and reduce the number of chronic seizures. CHA1 is a compound combination our lab recently discovered composed of epigallocatechin-3-gallate (EGCG) and decitabine (DAC), both of which are likely to cross the blood-brain barrier. CHA1 suppressed the Wnt-driven aerobic glycolysis, mTOR signaling, and astrogliosis observed in the epileptogenic period. Remarkably, inhibition of the epileptogenic program by CHA1 also dramatically reduced the development of chronic seizures, as well as the chronic metabolic and mTOR sequalae defined in these models. Thus, by modifying the molecular events early in epileptogenesis, CHA1 treatment had a significant and longterm effect in preventing or reducing the chronic epilepsy phenotype. Finally, the linkage of the molecular events of epileptogenesis with chronic disease suggests additional modes of intervention that may also have neuroprotective properties to prevent epilepsy etiology and development.