D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury.

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.

• Authors: Rami Yaka, Anat Biegon, Nikolaos Grigoriadis, Constantina Simeonidou, Savvas Grigoriadis, Alexander G Alexandrovich, Henri Matzner, Johanna Schumann, Victoria Trembovler, Jeanna Tsenter, Esther Shohami
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 21 Issue 9 Pg. 2033-41 (Jul 2007) ISSN: 1530-6860 [Electronic] United States
• PMID: 17351125 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Brain-Derived Neurotrophic Factor
• Excitatory Amino Acid Agonists
• Neuroprotective Agents
• Receptors, N-Methyl-D-Aspartate
• Synaptophysin
• Cycloserine

Topics

• Animals
• Astrocytes (metabolism, pathology)
• Brain Injuries (drug therapy, etiology, physiopathology)
• Brain-Derived Neurotrophic Factor (biosynthesis, genetics)
• Cycloserine (pharmacology, therapeutic use)
• Drug Evaluation, Preclinical
• Excitatory Amino Acid Agonists (pharmacology, therapeutic use)
• Excitatory Postsynaptic Potentials (drug effects)
• Head Injuries, Closed (complications)
• Hippocampus (drug effects, physiopathology, ultrastructure)
• Long-Term Potentiation (drug effects)
• Male
• Mice
• Microglia (metabolism, pathology)
• Motor Activity (drug effects)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Receptors, N-Methyl-D-Aspartate (agonists, physiology)
• Recognition, Psychology (drug effects)
• Single-Blind Method
• Synaptophysin (biosynthesis, genetics)