Harmine, a natural beta-carboline alkaloid, upregulates astroglial glutamate transporter expression

Yun Li, Rita Sattler, Eun Ju Yang, Alice Nunes, Yoko Ayukawa, Sadia Akhtar, Grace Ji, Ping Wu Zhang, Jeffrey D. Rothstein

Research output: Contribution to journalArticlepeer-review

Abstract

Glutamate is the predominant excitatory amino acid neurotransmitter in the mammalian central nervous system (CNS). Glutamate transporter EAAT2/GLT-1 is the physiologically dominant astroglial protein that inactivates synaptic glutamate. Previous studies have shown that EAAT2 dysfunction leads to excessive extracellular glutamate and may contribute to various neurological disorders including amyotrophic lateral sclerosis (ALS). The recent discovery of the neuroprotective properties of ceftriaxone, a beta lactam antibiotic, suggested that increasing EAAT2/GLT-1 gene expression might be beneficial in ALS and other neurological/psychiatric disorders by augmenting astrocytic glutamate uptake. Here we report our efforts to develop a new screening assay for identifying compounds that activate EAAT2 gene expression. We generated fetal derived-human immortalized astroglial cells that are stably expressing a firefly luciferase reporter under the control of the human EAAT2 promoter. When screening a library of 1040 FDA approved compounds and natural products, we identified harmine, a naturally occurring beta-carboline alkaloid, as one of the top hits for activating the EAAT2 promoter. We further tested harmine in our in vitro cell culture systems and confirmed its ability to increase EAAT2/GLT1 gene expression and functional glutamate uptake activity. We next tested its efficacy in both wild type animals and in an ALS animal model of disease and demonstrated that harmine effectively increased GLT-1 protein and glutamate transporter activity in vivo. Our studies provide potential novel neurotherapeutics by modulating the activity of glutamate transporters via gene activation. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'.

Original languageEnglish (US)
Pages (from-to)1168-1175
Number of pages8
JournalNeuropharmacology
Volume60
Issue number7-8
DOIs
StatePublished - Jun 2011

Keywords

  • ALS
  • Astroglia
  • EAAT2
  • GLT-1
  • Glutamate transporter
  • Harmine

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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