Development of Pyridazine-Derivatives for the Treatment of Neurological Disorders
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The Ohio State University / OhioLINK
2019
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=osu1545904228813231 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu15459042288132312021-08-03T07:09:26Z Development of Pyridazine-Derivatives for the Treatment of Neurological Disorders Foster, Joshua B. Neurosciences Alzheimers disease excitatory amino acid transporter 2 EAAT2 pyridazine derivatives tau pathology drug development drug discovery translational neuroscience Excitatory amino acid transporter 2 (EAAT2) is the principle glutamate transporter in the adult forebrain and plays a primary role in the regulation of glutamate homeostasis by maintaining normal glutamate signaling. Glutamate is a common excitatory neurotransmitter in the forebrain and certain basal levels are normal. However, excessive glutamate concentrations or prolonged glutamate signaling can be pathological and lead to excitotoxicity which is characterized by synaptic damage and eventually neuronal death. Many neurological and neurodegenerative diseases, from different etiologies, share a common feature of excess synaptic glutamate concentrations and reduced EAAT2 protein expression. Considering EAAT2’s prominent role in glutamate homeostasis, EAAT2 has been a target for drug development over the past 20 years to prevent excitotoxicity. We have focused on the development of small-molecule compounds, pyridazine-derivatives, that increase translation of EAAT2 to enhance glutamate uptake, normalize glutamate homeostasis, and provide therapeutic efficacy in neurodegenerative disease. Herein, this body of work attempts to better clarify the compound mechanism of action as well as to determine the potential of advanced analogues for efficacy in neurodegenerative disease models for translation to the clinic. First, we show that advanced pyridazine-derivatives are exceptionally efficacious at protecting against and delaying the progression of mutant tau-mediated pathology in an aggressive mouse model of Alzheimer’s disease. Second, we had previously shown that pyridazine derivatives induce EAAT2 through translation induction. Here, we show that this occurs locally, in a non-canonical manner, in perisynaptic processes, intimately close to the synapse where EAAT2 exerts its glutamate uptake function. Furthermore, a subset of PAP proteins in addition to EAAT2 are locally translated in response to compound and may facilitate enhanced synaptic plasticity. Finally, we attempt to identify the compound target and describe other aspects of the compound mechanism of action including two novel functions of pyridazine-derivatives: protection against oxidative stress and negative regulation of EAAT2 under certain conditions. The accumulation of information regarding the mechanism of action and the efficacy of pyridazine-derivatives in multiple animal models of neurodegeneration shows promise that these compounds may provide therapeutic efficacy in human clinical populations. 2019-08-28 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1545904228813231 http://rave.ohiolink.edu/etdc/view?acc_num=osu1545904228813231 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Neurosciences Alzheimers disease excitatory amino acid transporter 2 EAAT2 pyridazine derivatives tau pathology drug development drug discovery translational neuroscience |
| spellingShingle |
Neurosciences Alzheimers disease excitatory amino acid transporter 2 EAAT2 pyridazine derivatives tau pathology drug development drug discovery translational neuroscience Foster, Joshua B. Development of Pyridazine-Derivatives for the Treatment of Neurological Disorders |
| author |
Foster, Joshua B. |
| author_facet |
Foster, Joshua B. |
| author_sort |
Foster, Joshua B. |
| title |
Development of Pyridazine-Derivatives for the Treatment of Neurological Disorders |
| title_short |
Development of Pyridazine-Derivatives for the Treatment of Neurological Disorders |
| title_full |
Development of Pyridazine-Derivatives for the Treatment of Neurological Disorders |
| title_fullStr |
Development of Pyridazine-Derivatives for the Treatment of Neurological Disorders |
| title_full_unstemmed |
Development of Pyridazine-Derivatives for the Treatment of Neurological Disorders |
| title_sort |
development of pyridazine-derivatives for the treatment of neurological disorders |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2019 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1545904228813231 |
| work_keys_str_mv |
AT fosterjoshuab developmentofpyridazinederivativesforthetreatmentofneurologicaldisorders |
| _version_ |
1719454944137838592 |