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

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.

Correction: Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.

[This corrects the article DOI: 10.1371/journal.pone.0155711.].

Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.

Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis) show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR). However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi), become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi)). Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG)-a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF) 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.