title: Levetiracetam inhibits oligomeric Aβ-induced glutamate release from human astrocytes.
abstract: A recently identified mechanism for oligomeric Aβ-induced glutamate release from astrocytes involves intracellular Ca elevation, potentially by Ca-dependent vesicular release. Evidence suggests that levetiracetam (LEV; Keppra), an antiepileptic drug, can improve cognitive performance in both humans with mild cognitive impairment and animal models of Alzheimer disease. Because LEV acts by modulating neurotransmitter release from neurons by interaction with synaptic vesicles, we tested the effect of LEV on Aβ-induced astrocytic release of glutamate. We used a fluorescence resonance energy transfer-based glutamate sensor (termed SuperGluSnFR), whose structure is based on the ligand-binding site of glutamate receptors, to monitor glutamate release from primary cultures of human astrocytes exposed to oligomeric amyloid-β peptide 1-42 (Aβ42). We found that LEV (10 µM) inhibited oligomeric Aβ-induced astrocytic glutamate release. In addition, we show that this Aβ-induced glutamate release from astrocytes is sensitive to tetanus neurotoxin, an inhibitor of the vesicle release machinery. Taken together, our evidence suggests that LEV inhibits Aβ-induced vesicular glutamate release from astrocytes and thus may underlie, at least in part, the ability of LEV to reduce hyperexcitability in Alzheimer disease.
authors.affiliation: aNeurodegenerative Disease Center, Scintillon Institute bDepartment of Neurosciences, School of Medicine, University of California, San Diego cDel E. Webb Center for Neuroscience, Aging and Stem Cell Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Sanz-Blasco
authors.forename: Juan C
authors.initials: JC
authors.lastname: Piña-Crespo
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000077287:Levetiracetam; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D018697:Nootropic Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D008164:Luminescent Proteins; D018697:Nootropic Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D000077287:Levetiracetam; D002118:Calcium; D010889:Piracetam