Journal ArticleDOI
β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression
Jeffrey D. Rothstein,Sarjubhai Patel,Melissa R. Regan,Christine Haenggeli,Yanhua H. Huang,Dwight E. Bergles,Lin Jin,Margaret Dykes Hoberg,Svetlana Vidensky,Dorothy S. Chung,Shuy Vang Toan,Lucie I. Bruijn,Zao-Zhong Su,Pankaj Gupta,Paul B. Fisher +14 more
TLDR
Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, it is discovered that many β-lactam antibiotics are potent stimulators of GLT1 expression, and this action appears to be mediated through increased transcription of theGLT1 gene.Abstract:
Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.read more
Citations
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Astrocytes: biology and pathology
TL;DR: Astrocyte functions in healthy CNS, mechanisms and functions of reactive astrogliosis and glial scar formation, and ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions are reviewed.
Journal ArticleDOI
The Pharmacological Basis of Therapeutics
TL;DR: The Pharmacological Basis of Therapeutics, by Prof. Louis Goodman and Prof. Alfred Gilman, New York: The Macmillan Company, 1941, p.
Journal ArticleDOI
Molecular dissection of reactive astrogliosis and glial scar formation.
TL;DR: Developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis are reviewed and the potential to identify novel therapeutic molecular targets for diverse neurological disorders is highlighted.
Journal ArticleDOI
Astrocytes, from brain glue to communication elements: the revolution continues.
Andrea Volterra,Jacopo Meldolesi +1 more
TL;DR: The recent recognition that astrocytes are organized in separate territories and possess active properties — notably a competence for the regulated release of 'gliotransmitters', including glutamate — has enabled us to develop an understanding of previously unknown functions for astroCytes.
Journal ArticleDOI
ALS: a disease of motor neurons and their nonneuronal neighbors.
TL;DR: In this paper, a mutant superoxide dismutase (SOD1) was found to induce non-cell-autonomous motor neuron killing by an unknown gain of toxicity.
References
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Journal ArticleDOI
Goodman and Gilman's the Pharmacological Basis of Therapeutics
William H. Stigelman,Pharm D. +1 more
Journal ArticleDOI
The Pharmacological Basis of Therapeutics
TL;DR: The Pharmacological Basis of Therapeutics, by Prof. Louis Goodman and Prof. Alfred Gilman, New York: The Macmillan Company, 1941, p.
Journal ArticleDOI
Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate
Jeffrey D. Rothstein,Margaret Dykes-Hoberg,Carlos A. Pardo,Lynn A. Bristol,Lin Jin,Ralph W. Kuncl,Yoshikatsu Kanai,Matthias A. Hediger,Yanfeng Wang,Jerry P Schielke,Devin Franklin Welty +10 more
TL;DR: It is suggested that glial glutamate transporters provide the majority of functional glutamate transport and are essential for maintaining low extracellular glutamate and for preventing chronic glutamate neurotoxicity.
Journal ArticleDOI
Epilepsy and Exacerbation of Brain Injury in Mice Lacking the Glutamate Transporter GLT-1
Kohichi Tanaka,Kei Watase,Toshiya Manabe,Keiko Yamada,Masahiko Watanabe,Katsunobu Takahashi,Hisayuki Iwama,Toru Nishikawa,Nobutsune Ichihara,Tateki Kikuchi,Shigeru Okuyama,Naoya Kawashima,Seiji Hori,Misato Takimoto,Keiji Wada +14 more
TL;DR: Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury, which can be attributed to elevated levels of residual glutamate in the brains of these mice.
Journal ArticleDOI
Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis.
TL;DR: Developing C‐terminal, antioligopeptide antibodies that were specific for each glutamate transporter subtype found that GLT‐1 immunoreactive protein was severely decreased in ALS, both in motor cortex (71% decrease compared with control) and in spinal cord.