PMID- 32126102 OWN - NLM STAT- MEDLINE DCOM- 20200611 LR - 20200611 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 15 IP - 3 DP - 2020 TI - Hypothermia but not NMDA receptor antagonism protects against stroke induced by distal middle cerebral arterial occlusion in mice. PG - e0229499 LID - 10.1371/journal.pone.0229499 [doi] LID - e0229499 AB - Excitotoxicity mediated by the N-methyl-D-aspartate receptor (NMDAR) is believed to be a primary mechanism of neuronal injury following stroke. Thus, many drugs and therapeutic peptides were developed to inhibit either the NMDAR at the cell surface or its downstream intracellular death-signaling cascades. Nevertheless, the majority of focal ischemia studies concerning NMDAR antagonism were performed using the intraluminal suture-induced middle cerebral arterial occlusion (MCAO) model, which produces a large cortical and subcortical infarct leading to hypothalamic damage and fever in experimental animals. Here, we investigated whether NMDAR antagonism by drugs and therapeutic peptides was neuroprotective in a mouse model of distal MCAO (dMCAO), which produces a small cortical infarct sparing the hypothalamus and other subcortical structures. For establishment of this model, mice were subjected to dMCAO under normothermic conditions or body-temperature manipulations, and in the former case, their brains were collected at 3-72 h post-ischemia to follow the infarct development. These mice developed cortical infarction 6 h post-ischemia, which matured by 24-48 h post-ischemia. Consistent with the hypothesis that the delayed infarction in this model can be alleviated by neuroprotective interventions, hypothermia strongly protected the mouse brain against cerebral infarction in this model. To evaluate the therapeutic efficacy of NMDAR antagonism in this model, we treated the mice with MK801, Tat-NR2B9c, and L-JNKI-1 at doses that were neuroprotective in the MCAO model, and 30 min later, they were subjected to 120 min of dMCAO either in the awake state or under anesthesia with normothermic controls. Nevertheless, NMDAR antagonism, despite exerting pharmacological effects on mouse behavior, repeatedly failed to show neuroprotection against cerebral infarction in this model. The lack of efficacy of these treatments is reminiscent of the recurrent failure of NMDAR antagonism in clinical trials. While our data do not exclude the possibility that these treatments could be effective at a different dose or treatment regimen, they emphasize the need to test drug efficacy in different stroke models before optimal doses and treatment regimens can be selected for clinical trials. FAU - Liu, Che-Wei AU - Liu CW AD - Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. AD - School of Medicine, China Medical University, Taichung, Taiwan. FAU - Liao, Kate Hsiurong AU - Liao KH AD - Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. AD - Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan. FAU - Tseng, Hsin AU - Tseng H AD - School of Medicine, China Medical University, Taichung, Taiwan. FAU - Wu, Ching Mei AU - Wu CM AD - Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. FAU - Chen, Hsiao-Yun AU - Chen HY AD - Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. FAU - Lai, Ted Weita AU - Lai TW AUID- ORCID: 0000-0002-6229-4134 AD - Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan. AD - School of Medicine, China Medical University, Taichung, Taiwan. AD - Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. AD - Drug Development Center, China Medical University, Taichung, Taiwan. AD - Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200303 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (L-JNKI-1) RN - 0 (Neuroprotective Agents) RN - 0 (Peptides) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 6LR8C1B66Q (Dizocilpine Maleate) RN - D45TI2TWMA (Tat-NR2B9c) SB - IM MH - Animals MH - Cerebral Infarction/etiology/*prevention & control MH - Disease Models, Animal MH - Dizocilpine Maleate/*administration & dosage/pharmacology MH - Hypothermia, Induced/*methods MH - Infarction, Middle Cerebral Artery/complications/etiology/*therapy MH - Male MH - Mice MH - Neuroprotective Agents/administration & dosage/pharmacology MH - Peptides/administration & dosage/pharmacology MH - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors MH - Treatment Outcome PMC - PMC7053748 COIS- The authors have declared that no competing interests exist. EDAT- 2020/03/04 06:00 MHDA- 2020/06/12 06:00 PMCR- 2020/03/03 CRDT- 2020/03/04 06:00 PHST- 2019/07/15 00:00 [received] PHST- 2020/02/07 00:00 [accepted] PHST- 2020/03/04 06:00 [entrez] PHST- 2020/03/04 06:00 [pubmed] PHST- 2020/06/12 06:00 [medline] PHST- 2020/03/03 00:00 [pmc-release] AID - PONE-D-19-19948 [pii] AID - 10.1371/journal.pone.0229499 [doi] PST - epublish SO - PLoS One. 2020 Mar 3;15(3):e0229499. doi: 10.1371/journal.pone.0229499. eCollection 2020.