The glycolytic inhibitor 2-deoxyglucose as a novel therapeutic agent to prevent cortical network dysfunction after traumatic brain injury.
Koenig, Jenny.
2019
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Traumatic brain injury
(TBI) is a significant cause of disability worldwide, as it can cause a wide range of
chronic complications associated with disrupted cortical function. Multiple molecular,
cellular, and network pathologies occur following injury, but the pathophysiology of
post-TBI cortical dysfunction is not well-understood. Many studies have demonstrated
that GABAergic inhibitory ... read morenetwork function is compromised following TBI, which may
contribute to cortical hyperexcitability and motor, behavioral, and cognitive deficits.
The loss or dysfunction of inhibitory interneurons may also be epileptogenic, and thus,
could result in spontaneous new-onset seizure activity observed commonly after TBI, in a
condition known as post-traumatic epilepsy (PTE). Preserving the function of GABAergic
interneurons, therefore, is a rational therapeutic strategy to preserve cortical
function after TBI and prevent long-term clinical complications. Following TBI, there is
a complex landscape of metabolic changes that evolve over days and weeks. Based on rich
clinical and preclinical data of these post-TBI changes in glucose utilization, combined
with the success of metabolic therapies like the ketogenic diet in treating epilepsy,
interest has grown in determining whether manipulating metabolic activity following
traumatic brain injury may have therapeutic value to prevent post-traumatic
epileptogenesis. In this thesis, I explore whether the use of a glycolytic inhibitor,
2-deoxyglucose (2-DG), affects post-TBI cortical pathology. First, I outline the
therapeutic rationale behind this approach by examining changes in glucose utilization
and glycolytic activity in the brain following traumatic brain injury and during
seizures. In this section, I also outline potential paths forward to utilize glycolytic
inhibitors as a disease-modifying therapy for post-traumatic epilepsy. Then, I tested
whether the use of 2-DG attenuated cortical dysfunction after TBI in a mouse model of
focal brain contusion. Employing the controlled cortical impact (CCI) model of TBI, we
found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in
acute cortical slices 3-5 weeks after TBI. One week of in vivo 2-DG treatment
immediately after TBI prevented the development of epileptiform activity, restored
excitatory and inhibitory synaptic activity, and attenuated the loss of
parvalbumin-expressing inhibitory interneurons. Further, I found that acute in vitro
application of 2-DG decreased the excitability of excitatory neurons, but not inhibitory
interneurons, suggesting a possible cell type-specific mechanism for 2-DG's effects. In
summary, the glycolytic inhibitor 2-DG may have therapeutic potential to restore network
function following TBI.
Thesis (Ph.D.)--Tufts University, 2021.
Submitted to the Dept. of Neuroscience.
Advisor: Chris Dulla.
Committee: Jamie Maguire, Maribel Rios, Dong Kong, and Michael Whalen.
Keyword: Neurosciences.read less - ID:
- f1882038q
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