D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury.
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.
Yaka
Rami
R
Department of Pharmacology, School of Pharmacy, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. yaka@md.huji.ac.il
Biegon
Anat
A
Grigoriadis
Nikolaos
N
Simeonidou
Constantina
C
Grigoriadis
Savvas
S
Alexandrovich
Alexander G
AG
Matzner
Henri
H
Schumann
Johanna
J
Trembovler
Victoria
V
Tsenter
Jeanna
J
Shohami
Esther
E
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
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; D003523:Cycloserine