Identifying novel therapeutic targets for seizures and brain cancers
type: CreativeWork
description: Epilepsy describes a range of conditions characterised by unprovoked recurring seizures that are due to multiple factors including the excitatory neurotransmitter glutamate. A subgroup of patients with epilepsy may not respond to systemic treatment and therefore would become candidates for surgical therapy. A less invasive approach is vagal nerve stimulation, which I demonstrated is safe and effective in 100 patients, in the first UK based large case series. Another group of patients that suffer from intractable epilepsy are those with tumour associated seizures (TAS). In particular, patients diagnosed with glioblastoma multiforme can initially present with unexplained seizures or develop seizures later in the course of the disease. TAS is often pharmaco-resistant and treatment options are limited. Animal models of TAS demonstrated that the systemic Xc- cysteine-glutamate exchange transporter (XCT) antagonist sulfasalazine reduced the frequency of seizures. In human studies of TAS, increased levels of glutamate, reduced excitatory amino acid transporter 2 (EAAT2) expression and reduced XCT were associated with greater frequency of TAS. We found that EAAT2 single nucleotide mutations correlated with an increased susceptibility to cerebral palsy in pre-term infants, implicating glutamate excess as the underlying cause. Together with evidence of downregulation of EAAT at the peri-tumoural region in TAS, it became evident that glutamate mediated excitotoxicity caused by dysfunctional EAAT2 may be a therapeutic target in such diseases. Therefore, I investigated strategies to modulate the expression of EAAT2, identifying peroxisome proliferator gamma (PPARγ) agonists as a promising candidate. I utilised Immortalised glioblastoma cell lines to investigate the role of the PPARγ agonist pioglitazone on glutamate transport in vitro. Pioglitazone was chosen for its established safety profile in type 2 diabetes and widely reported anti-neoplastic effects. I demonstrated that pi…
abstract: Epilepsy describes a range of conditions characterised by unprovoked recurring seizures that are due to multiple factors including the excitatory neurotransmitter glutamate. A subgroup of patients with epilepsy may not respond to systemic treatment and therefore would become candidates for surgical therapy. A less invasive approach is vagal nerve stimulation, which I demonstrated is safe and effective in 100 patients, in the first UK based large case series. Another group of patients that suffer from intractable epilepsy are those with tumour associated seizures (TAS). In particular, patients diagnosed with glioblastoma multiforme can initially present with unexplained seizures or develop seizures later in the course of the disease. TAS is often pharmaco-resistant and treatment options are limited. Animal models of TAS demonstrated that the systemic Xc- cysteine-glutamate exchange transporter (XCT) antagonist sulfasalazine reduced the frequency of seizures. In human studies of TAS, increased levels of glutamate, reduced excitatory amino acid transporter 2 (EAAT2) expression and reduced XCT were associated with greater frequency of TAS. We found that EAAT2 single nucleotide mutations correlated with an increased susceptibility to cerebral palsy in pre-term infants, implicating glutamate excess as the underlying cause. Together with evidence of downregulation of EAAT at the peri-tumoural region in TAS, it became evident that glutamate mediated excitotoxicity caused by dysfunctional EAAT2 may be a therapeutic target in such diseases. Therefore, I investigated strategies to modulate the expression of EAAT2, identifying peroxisome proliferator gamma (PPARγ) agonists as a promising candidate. I utilised Immortalised glioblastoma cell lines to investigate the role of the PPARγ agonist pioglitazone on glutamate transport in vitro. Pioglitazone was chosen for its established safety profile in type 2 diabetes and widely reported anti-neoplastic effects. I demonstrated that pi…
author: Ching, Jared
language: eng
keywords: Epilepsy, Glutamate, Tumour associated seizures, Pioglitazone, Neural stem cells, Glioblastoma, Electrotaxis
date published: 2022-01-01T08:00:00Z
date modified: 2026-07-24T03:50:32Z
provider: University of Plymouth
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Plymouth