A New Molecular Mechanism Underlying Epileptogenesis, and a Novel Therapeutic Strategy for Treating Epilepsy
Alqurashi, Roaya.
2020
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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 ... read moreseizures (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 long-term 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.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: Amy Yee.
Committee: Eric Paulson, James Baleja, Jamie Maguire, and David Greenblatt.
Keywords: Pharmacology, and Neurosciences.
Thesis (Ph.D.)--Tufts University, 2020.read less - ID:
- xg94j406m
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