PMID- 27693471
OWN - NLM
STAT- MEDLINE
DCOM- 20171030
LR  - 20171030
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Linking)
VI  - 339
DP  - 2016 Dec 17
TI  - Serine racemase inhibition induces nitric oxide-mediated neurovascular protection 
      during cerebral ischemia.
PG  - 139-149
LID - S0306-4522(16)30483-3 [pii]
LID - 10.1016/j.neuroscience.2016.09.036 [doi]
AB  - There are no effective neuroprotectant drugs for acute cerebral ischemia. Serine 
      racemase (SR) synthesizes d-serine, which is involved in N-methyl-d-aspartate 
      (NMDA) receptor-induced neurotoxicity. Recently, SR deletion was reported to 
      protect against focal cerebral ischemia. However, regulatory mechanisms 
      controlling SR-activity in the neurovascular unit (NVU) during cerebral ischemia 
      remain to be clarified. We investigated the effects of SR inhibition on 
      neurovascular protection after ischemia. The SR inhibitor phenazine methosulfate 
      (PMS) alleviated neuronal damage in an ex vivo ischemic model (oxygen glucose 
      deprivation [OGD]) using primary neuronal cultures, and in an in vivo mouse model 
      of ischemia (middle cerebral artery occlusion [MCAO]). Ischemic preconditioning 
      (IP) and PMS-treatment inhibited SR phosphorylation after ischemia ex vivo. In 
      addition, SR phosphorylation after MCAO was also decreased in PMS-treated mice. 
      Reductions in regional cerebral blood flow (CBF) after MCAO were improved by 
      administration of PMS. Treatment with PMS increased phosphorylation of 
      endothelial nitric oxide synthase (eNOS) in the ischemic core and penumbra 
      region. In neuron-endothelial cell co-cultures, PMS promoted nitric oxide 
      production after OGD. These findings indicate that SR inhibition acts as a 
      neuroprotectant in the NVU and ameliorant of CBF abnormalities post-stroke. Thus, 
      pharmacologic SR inhibition has potential clinical applications.
CI  - Copyright (c) 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
FAU - Watanabe, Akihiro
AU  - Watanabe A
AD  - Department of Neurology, Osaka University Graduate School of Medicine, 2-2 
      Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: 
      watanabe@neurol.med.osaka-u.ac.jp.
FAU - Sasaki, Tsutomu
AU  - Sasaki T
AD  - Department of Neurology, Osaka University Graduate School of Medicine, 2-2 
      Yamadaoka, Suita, Osaka 565-0871, Japan.
FAU - Yukami, Toshiro
AU  - Yukami T
AD  - Department of Neurology, Osaka University Graduate School of Medicine, 2-2 
      Yamadaoka, Suita, Osaka 565-0871, Japan.
FAU - Kanki, Hideaki
AU  - Kanki H
AD  - Department of Neurology, Osaka University Graduate School of Medicine, 2-2 
      Yamadaoka, Suita, Osaka 565-0871, Japan.
FAU - Sakaguchi, Manabu
AU  - Sakaguchi M
AD  - Department of Neurology, Osaka University Graduate School of Medicine, 2-2 
      Yamadaoka, Suita, Osaka 565-0871, Japan.
FAU - Takemori, Hiroshi
AU  - Takemori H
AD  - Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical 
      Innovation, Saito, Ibaraki, Osaka 567-0085, Japan.
FAU - Kitagawa, Kazuo
AU  - Kitagawa K
AD  - Department of Neurology, Tokyo Women's Medical University, 8-1 Kawada-cho, 
      Shinjuku-ku, Tokyo 162-8666, Japan.
FAU - Mochizuki, Hideki
AU  - Mochizuki H
AD  - Department of Neurology, Osaka University Graduate School of Medicine, 2-2 
      Yamadaoka, Suita, Osaka 565-0871, Japan.
LA  - eng
PT  - Journal Article
DEP - 20160928
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Neuroprotective Agents)
RN  - 299-11-6 (Methylphenazonium Methosulfate)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos3 protein, mouse)
RN  - EC 5.1.- (Racemases and Epimerases)
RN  - EC 5.1.1.16 (serine racemase)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Brain Ischemia/*drug therapy/enzymology/pathology
MH  - Cell Hypoxia/drug effects/physiology
MH  - Cell Line
MH  - Cells, Cultured
MH  - Cerebral Cortex/drug effects/enzymology/pathology
MH  - Cerebrovascular Circulation/drug effects/physiology
MH  - Disease Models, Animal
MH  - Glucose/deficiency
MH  - Male
MH  - Methylphenazonium Methosulfate/*pharmacology
MH  - Mice, Inbred C57BL
MH  - Neurons/drug effects/enzymology/pathology
MH  - Neuroprotective Agents/*pharmacology
MH  - Nitric Oxide/*metabolism
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - Phosphorylation/drug effects
MH  - Racemases and Epimerases/*antagonists & inhibitors/metabolism
MH  - Random Allocation
MH  - Rats, Wistar
OTO - NOTNLM
OT  - brain ischemia
OT  - endothelium
OT  - ischemic preconditioning and induced tolerance
OT  - nitric oxide
OT  - serine racemase
EDAT- 2016/11/05 06:00
MHDA- 2017/10/31 06:00
CRDT- 2016/11/05 06:00
PHST- 2016/03/04 00:00 [received]
PHST- 2016/09/21 00:00 [revised]
PHST- 2016/09/21 00:00 [accepted]
PHST- 2016/11/05 06:00 [pubmed]
PHST- 2017/10/31 06:00 [medline]
PHST- 2016/11/05 06:00 [entrez]
AID - S0306-4522(16)30483-3 [pii]
AID - 10.1016/j.neuroscience.2016.09.036 [doi]
PST - ppublish
SO  - Neuroscience. 2016 Dec 17;339:139-149. doi: 10.1016/j.neuroscience.2016.09.036. 
      Epub 2016 Sep 28.