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Cellular origin and regulation of D- and L-serine in in vitro and in vivo models of cerebral ischemia.

Abstract
D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-serine from L-serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-serine remain elusive. The D-/L-serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-serine is derived from neurons, while L-serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3-PGDH), which synthesizes L-serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH.
AuthorsTakato Abe, Masataka Suzuki, Jumpei Sasabe, Shinichi Takahashi, Miyuki Unekawa, Kyoko Mashima, Takuya Iizumi, Kenji Hamase, Ryuichi Konno, Sadakazu Aiso, Norihiro Suzuki
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 34 Issue 12 Pg. 1928-35 (Dec 2014) ISSN: 1559-7016 [Electronic] United States
PMID25294127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Receptors, N-Methyl-D-Aspartate
  • Serine
  • Phosphoglycerate Dehydrogenase
  • Racemases and Epimerases
Topics
  • Animals
  • Animals, Newborn
  • Astrocytes (cytology, metabolism)
  • Brain Ischemia (metabolism)
  • Disease Models, Animal
  • Female
  • Humans
  • Infarction, Middle Cerebral Artery (metabolism)
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons (cytology, metabolism)
  • Phosphoglycerate Dehydrogenase (metabolism)
  • Pregnancy
  • Primary Cell Culture
  • Racemases and Epimerases (genetics, metabolism)
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate (metabolism)
  • Serine (chemistry, metabolism)
  • Stereoisomerism
  • Substrate Specificity

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