Journal article
Novel Positive Allosteric Modulators of Glutamate Transport Have Neuroprotective Properties in an in Vitro Excitotoxic Model
ACS chemical neuroscience, v 10(8), pp 3437-3453
21 Aug 2019
PMID: 31257852
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsy, and several neurodegenerative disorders. EAAT2 is the main transporter subtype responsible for glutamate clearance in the brain, and plays a key role in regulating neurotransmission and preventing excitotoxicity. Therefore, compounds that increase the activity of EAAT2 have therapeutic potential for neuroprotection. In previous studies, we used virtual screening approaches to identify novel positive allosteric modulators (PAMs) of EAAT2. These compounds were shown to selectively increase the activity of EAAT2 and increase
of transport, without changing substrate affinity. In this work, our major effort was to investigate whether increasing the activity of EAAT2 by allosteric modulation would translate to neuroprotection in in vitro primary culture models of excitotoxicity. To investigate potential neuroprotective effects of one EAAT2 PAM, GT949, we subjected cultures to acute and prolonged excitotoxic insults by exogenous application of glutamate, or oxidative stress by application of hydrogen peroxide. GT949 administration did not result in neuroprotection in the oxidative stress model, likely due to damage of the glutamate transporters. However, GT949 displayed neuroprotective properties after acute and prolonged glutamate-mediated excitotoxicity. We propose that this compound prevents excess glutamate signaling by increasing the rate of glutamate clearance by EAAT2, thereby preventing excitotoxic damage and cell death. This novel class of compounds is therefore an innovative approach for neuroprotection with potential for translation in in vivo animal models of excitotoxicity.
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Details
- Title
- Novel Positive Allosteric Modulators of Glutamate Transport Have Neuroprotective Properties in an in Vitro Excitotoxic Model
- Creators
- Romulo Martelli Falcucci - Department of Pharmacology and Physiology , Drexel University College of Medicine , Philadelphia , Pennsylvania 19102 , United StatesRyan Wertz - Department of Pharmacology and Physiology , Drexel University College of Medicine , Philadelphia , Pennsylvania 19102 , United StatesJennifer Leigh Green - Department of Pharmacology and Physiology , Drexel University College of Medicine , Philadelphia , Pennsylvania 19102 , United StatesOlimpia Meucci - Department of Pharmacology and Physiology , Drexel University College of Medicine , Philadelphia , Pennsylvania 19102 , United StatesJoseph Salvino - The Wistar Institute , Philadelphia , Pennsylvania 19104 , United StatesAndréia Cristina Karklin Fontana - Department of Pharmacology and Physiology , Drexel University College of Medicine , Philadelphia , Pennsylvania 19102 , United States
- Publication Details
- ACS chemical neuroscience, v 10(8), pp 3437-3453
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- R01 DA032444 / NIDA NIH HHS R37 DA015014 / NIDA NIH HHS R01 DA015014 / NIDA NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Accelerated Career Entry Bachelor of Science in Nursing (BSN); Pharmacology and Physiology
- Web of Science ID
- WOS:000482546100018
- Scopus ID
- 2-s2.0-85071702441
- Other Identifier
- 991014878289404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Medicinal
- Neurosciences