Abstract
Traumatic brain injury triggers a massive glutamate efflux, activation of NMDA receptor channels, and cell death. Recently, we reported that NMDA receptors in mice are down-regulated from hours to days following closed head injury (CHI), and treatment with NMDA improved recovery of motor and cognitive functions up to 14 d post-injury. Here we show that a single injection of a low dose of D-cycloserine (DCS), a partial NMDA receptor agonist, in CHI mice 24 h post-injury, resulted in a faster and greater recovery of motor and memory functions as assessed by neurological severity score and object recognition tests, respectively. Moreover, DCS treatment of CHI mice led to a significant improvement of hippocampal long-term potentiation (LTP) in the CA1 region that was completely blunted in CHI control mice. However, DCS did not improve CHI-induced impairment in synaptic glutamate release measured by paired pulse facilitation (PPF) ratio in hippocampal CA1 region. Finally, CHI-induced reduction of brain-derived neurotrophic factor (BDNF) was fully restored following DCS treatment. Since DCS is in clinical use for other indications, the present study offers a novel approach to treat human brain injury.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Astrocytes / metabolism
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Astrocytes / pathology
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Brain Injuries / drug therapy*
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Brain Injuries / etiology
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Brain Injuries / physiopathology
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Brain-Derived Neurotrophic Factor / biosynthesis
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Brain-Derived Neurotrophic Factor / genetics
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Cycloserine / pharmacology
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Cycloserine / therapeutic use*
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Drug Evaluation, Preclinical
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Agonists / therapeutic use*
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Excitatory Postsynaptic Potentials / drug effects
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Head Injuries, Closed / complications*
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Hippocampus / drug effects
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Hippocampus / physiopathology
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Hippocampus / ultrastructure
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Long-Term Potentiation / drug effects*
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Male
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Mice
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Microglia / metabolism
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Microglia / pathology
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Motor Activity / drug effects
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use*
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Receptors, N-Methyl-D-Aspartate / agonists*
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Receptors, N-Methyl-D-Aspartate / physiology
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Recognition, Psychology / drug effects
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Single-Blind Method
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Synaptophysin / biosynthesis
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Synaptophysin / genetics
Substances
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Brain-Derived Neurotrophic Factor
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Excitatory Amino Acid Agonists
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Neuroprotective Agents
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Receptors, N-Methyl-D-Aspartate
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Synaptophysin
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Cycloserine