title: 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.affiliation: Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. yaka@md.huji.ac.il
authors.forename: Rami
authors.initials: R
authors.lastname: Yaka
authors.forename: Anat
authors.initials: A
authors.lastname: Biegon
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Grigoriadis
authors.forename: Constantina
authors.initials: C
authors.lastname: Simeonidou
authors.forename: Savvas
authors.initials: S
authors.lastname: Grigoriadis
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Alexandrovich
authors.forename: Henri
authors.initials: H
authors.lastname: Matzner
authors.forename: Johanna
authors.initials: J
authors.lastname: Schumann
authors.forename: Victoria
authors.initials: V
authors.lastname: Trembovler
authors.forename: Jeanna
authors.initials: J
authors.lastname: Tsenter
authors.forename: Esther
authors.initials: E
authors.lastname: Shohami
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D003523:Cycloserine / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D016489:Head Injuries, Closed / Q000150:complications*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects; D016037:Single-Blind Method; D016708:Synaptophysin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; D003523:Cycloserine