PMID- 29648983 OWN - NLM STAT- MEDLINE DCOM- 20191106 LR - 20191106 IS - 1557-9042 (Electronic) IS - 0897-7151 (Linking) VI - 35 IP - 14 DP - 2018 Jul 15 TI - Enhancement of Brain d-Serine Mediates Recovery of Cognitive Function after Traumatic Brain Injury. PG - 1667-1680 LID - 10.1089/neu.2017.5561 [doi] AB - Cognitive deficits, especially memory loss, are common and devastating neuropsychiatric sequelae of traumatic brain injury (TBI). The deficits may persist for years and may be accompanied by increased risk of developing early- onset dementia. Past attempts to reverse the neuropathological effects of brain injury with glutamate-N-methyl-d-aspartate (NMDA) antagonists failed to show any benefits or worsened the outcome, suggesting that activation, rather than blockage, of the NMDA receptor (NMDAR) may be useful in the subacute period after TBI and stroke. Activation of the NMDAR requires occupation of the glycine-modulatory site by co-agonists to achieve its synaptic functions. Glycine and d-serine are endogenous ligands/co-agonists of synaptic NMDARs in many areas of the mature brain. The aim of the present study was to evaluate the effect of 6-chlorobenzo(d)isoxazol-3-ol (CBIO), an inhibitor of D-amino acid oxidase (DAAO), which degrades d-serine, on cognitive outcome in a mouse model of TBI. Because treating TBI animals with CBIO elevates the endogenous levels of d-serine, we compared this novel treatment with treatment by exogenous d-serine alone and combined with CBIO. The results show that a single treatment (24 h post-injury) with CBIO in the mouse model of closed head injury significantly improves cognitive and motor function, and decreases lesion volume and the inflammatory response. Moreover, the compound proved to be neuroprotective, as the hippocampal volume and the number of neurons in hippocampal regions increased. Treatment with CBIO boosted the NR1 and phospho- NR1 subunits of the NMDAR and affected the CREB, phospho-CREB, and brain-derived neurotropic factor (BDNF) pathways. These findings render CBIO a promising, novel treatment for cognitive impairment following TBI. FAU - Liraz-Zaltsman, Sigal AU - Liraz-Zaltsman S AD - 1 The Joseph Sagol Neuroscience Center, Sheba Medical Center , Tel Hashomer, Israel . AD - 2 Department of Pharmacology, Institute for Drug Research, Hebrew University , Jerusalem, Israel . FAU - Slusher, Barbara AU - Slusher B AD - 3 Johns Hopkin Drug Discovery and Department of Neurology, Johns Hopkins School of Medicine , Baltimore, Maryland. FAU - Atrakchi-Baranes, Dana AU - Atrakchi-Baranes D AD - 1 The Joseph Sagol Neuroscience Center, Sheba Medical Center , Tel Hashomer, Israel . FAU - Rosenblatt, Kineret AU - Rosenblatt K AD - 4 Department of Pathology, Sheba Medical Center , Tel Hashomer, Israel . FAU - Friedman Levi, Yael AU - Friedman Levi Y AD - 2 Department of Pharmacology, Institute for Drug Research, Hebrew University , Jerusalem, Israel . FAU - Kesner, Efrat AU - Kesner E AD - 2 Department of Pharmacology, Institute for Drug Research, Hebrew University , Jerusalem, Israel . FAU - Silva, Alcino J AU - Silva AJ AD - 5 Integrative Center for Learning and Memory Brain Research Institute, University of California , Los Angeles, California. FAU - Biegon, Anat AU - Biegon A AD - 6 Department of Radiology and Neurology, Stony Brook University School of Medicine , Stony Brook, New York. FAU - Shohami, Esther AU - Shohami E AD - 2 Department of Pharmacology, Institute for Drug Research, Hebrew University , Jerusalem, Israel . LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180430 PL - United States TA - J Neurotrauma JT - Journal of neurotrauma JID - 8811626 RN - 0 (5-chlorobenzo(d)isoxazol-3-ol) RN - 0 (Isoxazoles) RN - 0 (Neuroprotective Agents) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 452VLY9402 (Serine) SB - IM MH - Animals MH - *Brain Injuries, Traumatic/metabolism/physiopathology MH - Cognition/drug effects MH - Cognition Disorders/etiology MH - Isoxazoles/*pharmacology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuroprotective Agents/*pharmacology MH - Receptors, N-Methyl-D-Aspartate/agonists/*drug effects MH - Recovery of Function/*drug effects MH - Serine/*metabolism/pharmacology OTO - NOTNLM OT - CBIO OT - NMDARs OT - TBI OT - cognitive deficits OT - d-cycloserine EDAT- 2018/04/13 06:00 MHDA- 2019/11/07 06:00 CRDT- 2018/04/13 06:00 PHST- 2018/04/13 06:00 [pubmed] PHST- 2019/11/07 06:00 [medline] PHST- 2018/04/13 06:00 [entrez] AID - 10.1089/neu.2017.5561 [doi] PST - ppublish SO - J Neurotrauma. 2018 Jul 15;35(14):1667-1680. doi: 10.1089/neu.2017.5561. Epub 2018 Apr 30.