Enhancement of Brain d-Serine Mediates Recovery of Cognitive Function after Traumatic Brain Injury.

Abstract

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.

• Authors: Sigal Liraz-Zaltsman, Barbara Slusher, Dana Atrakchi-Baranes, Kineret Rosenblatt, Yael Friedman Levi, Efrat Kesner, Alcino J Silva, Anat Biegon, Esther Shohami
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 35 Issue 14 Pg. 1667-1680 (07 15 2018) ISSN: 1557-9042 [Electronic] United States
• PMID: 29648983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-chlorobenzo(d)isoxazol-3-ol
• Isoxazoles
• Neuroprotective Agents
• Receptors, N-Methyl-D-Aspartate
• Serine

Topics

• Animals
• Brain Injuries, Traumatic (metabolism, physiopathology)
• Cognition (drug effects)
• Cognition Disorders (etiology)
• Isoxazoles (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (pharmacology)
• Receptors, N-Methyl-D-Aspartate (agonists, drug effects)
• Recovery of Function (drug effects)
• Serine (metabolism, pharmacology)