In Vitro Cortical Networks for Disease Modeling and Drug Evaluation Page: 2
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Wu, Calvin. In Vitro Cortical Networks for Disease Modeling and Drug Evaluation.
Doctor of Philosophy (Biological Sciences), December 2013, 67 pp., 20 figures, references, 150
In translational research, disease models in preclinical studies are used as media for
discovery of drugs or novel therapeutics. Development of in vitro models for various
neurological diseases that enable efficient pharmacological or toxicological screening has been
ongoing but challenging. Recognizing the potential benefit of in vitro disease models,
dysfunctions in the cortical neuronal networks were induced to mimic the functional pathology
of neurological symptoms using microelectrode arrays. Two different disease states - tinnitus
and excitotoxicity - were investigated and discussed. In this model, pentylenetetrazol-induced
increase in spontaneous firing rate and synchrony in the auditory cortical networks was used as
correlate of tinnitus. Potential tinnitus treatment drugs from several different classes - including
the novel class of potassium channel openers - were screened and quantified. The potential
therapeutic values of these drugs were also discussed as the basis for drug repurposing.
Functional excitotoxicity was induced by cisplatin (a cancer drug that causes neurological side-
effects) and glutamate (the major excitatory neurotransmitter). As proof-of-principle that the
model may contribute to expediting the development of therapeutics, cisplatin excitotoxicity was
prevented by the antioxidant D-methionine, while glutamate excitotoxicity was prevented by
ceftriaxone (a modulator of a glutamate reuptake transporter). In the latter part of the study, with
results linking two of the screened drugs L-carnitine and D-methionine to GABAA receptor
activation, it was demonstrated that this model not only served as an efficient drug-screening
platform, but can be utilized to functionally investigate the underlying mechanism of drugs. In
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Wu, Calvin. In Vitro Cortical Networks for Disease Modeling and Drug Evaluation, thesis, December 2013; Denton, Texas. (digital.library.unt.edu/ark:/67531/metadc407860/m1/2/: accessed February 17, 2019), University of North Texas Libraries, Digital Library, digital.library.unt.edu; .