Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke

Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces isch...

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Bibliographic Details
Published in:PloS one 2011-08, Vol.6 (8), p.e22135-e22135
Main Authors: Harvey, Brandon K, Airavaara, Mikko, Hinzman, Jason, Wires, Emily M, Chiocco, Matthew J, Howard, Douglas B, Shen, Hui, Gerhardt, Greg, Hoffer, Barry J, Wang, Yun
Format: Article
Language:English
Subjects:
Amino Acid Transport System X-AG - metabolism
Amino acids
Amperometry
Animal behavior
Animals
Behavior, Animal - physiology
Biology
Brain
Brain damage
Brain Infarction - complications
Brain Infarction - pathology
Brain Infarction - physiopathology
Brain injuries
Brain Injuries - complications
Brain Injuries - pathology
Brain Injuries - physiopathology
Brain Injuries - prevention & control
Brain injury
Brain Ischemia - complications
Brain Ischemia - pathology
Brain Ischemia - physiopathology
Brain Ischemia - prevention & control
Cell death
Cerebral blood flow
Cerebral Cortex - metabolism
Cerebral Cortex - pathology
Cerebral Cortex - physiopathology
Cerebral infarction
Cortex
Damage assessment
Data recovery
Deoxyribonucleic acid
Dependovirus
Disease Models, Animal
DNA
DNA fragmentation
Electrical measurement
Excitotoxicity
Gene Expression Regulation
Gene therapy
Gene transfer
Glutamate
Glutamates - metabolism
Glutamic acid transporter
Head injuries
HEK293 Cells
Hostages
Humans
In Situ Nick-End Labeling
In vivo methods and tests
Infarction
Infarction, Middle Cerebral Artery - complications
Infarction, Middle Cerebral Artery - pathology
Infarction, Middle Cerebral Artery - physiopathology
Injuries
Injury prevention
Ischemia
Male
Microdialysis
Neurophysiology
Occlusion
Overexpression
Overflow
Pathogenesis
Rats
Rats, Inbred F344
Recovery of Function - physiology
Stroke
Stroke - complications
Stroke - pathology
Stroke - physiopathology
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Summary:Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces ischemic brain injury in a rat model of stroke. We generated an adeno-associated viral (AAV) vector expressing the rat GLT-1 cDNA (AAV-GLT1). Functional expression of AAV-GLT1 was confirmed by increased glutamate clearance rate in non-stroke rat brain as measured by in vivo amperometry. AAV-GLT1 was injected into future cortical region of infarction 3 weeks prior to 60 min middle cerebral artery occlusion (MCAo). Tissue damage was assessed at one and two days after MCAo using TUNEL and TTC staining, respectively. Behavioral testing was performed at 2, 8 and 14 days post-stroke. Animals receiving AAV-GLT1, compared to AAV-GFP, showed significant decreases in the duration and magnitude of extracellular glutamate, measured by microdialysis, during the 60 minute MCAo. A significant reduction in brain infarction and DNA fragmentation was observed in the region of AAV-GLT1 injection. Animals that received AAV-GLT1 showed significant improvement in behavioral recovery following stroke compared to the AAV-GFP group. We demonstrate that focal overexpression of the glutamate transporter, GLT-1, significantly reduces ischemia-induced glutamate overflow, decreases cell death and improves behavioral recovery. These data further support the role of glutamate in the pathogenesis of ischemic damage in brain and demonstrate that targeted gene delivery to decrease the ischemia-induced glutamate overflow reduces the cellular and behavioral deficits caused by stroke.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0022135