title: GlyT1 Inhibitor NFPS Exerts Neuroprotection via GlyR Alpha1 Subunit in the Rat Model of Transient Focal Cerebral Ischaemia and Reperfusion.
abstract: OBJECTIVE
  Glycine is a strychnine-sensitive inhibitory neurotransmitter in the central nervous system (CNS), especially in the spinal cord, brainstem, and retina. The objective of the present study was to investigate the potential neuroprotective effects of GlyT1 inhibitor N [3-(4'-fluorophenyl)-3-(4'-phenylphenoxy) propyl] sarcosine (NFPS) in the rat model of experimental stroke.
  
  
  METHODS
  In vivo ischaemia was induced by transient middle cerebral artery occlusion (tMCAO). The methods of Western Blotting, Nissl Staining and Morris water maze methods were applied to analyze the anti-ischaemia mechanism.
  
  
  RESULTS
  The results showed that high dose of NFPS (H-NFPS) significantly reduced infarct volume, neuronal injury and the expression of cleaved caspase-3, enhanced Bcl-2/Bax, and improved spatial learning deficits which were administered three hours after transient middle cerebral artery occlusion (tMCAO) induction in rats, while, low dose of NFPS (L-NFPS) exacerbated the injury of ischaemia. These findings suggested that low and high dose of NFPS produced opposite effects. Importantly, it was demonstrated that H-NFPS-dependent neuronal protection was inverted by salicylate (Sal), a specific GlyR x0251;1 antagonist. Such effects could probably be attributed to the enhanced glycine level in both synaptic and extrasynaptic clefts and the subsequently altered extrasynaptic GlyRs and their subtypes.
  
  
  CONCLUSIONS
  These data imply that GlyT1 inhibitor NFPS may be a novel target for clinical treatment of transient focal cerebral ischaemia and reperfusion which are associated with altered GlyR alpha 1 subunits.
authors.forename: Baosheng
authors.initials: B
authors.lastname: Huang
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Xie
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Lu
authors.forename: Tengda
authors.initials: T
authors.lastname: Qian
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.forename: Ronglan
authors.initials: R
authors.lastname: Zhu
authors.forename: Wan
authors.initials: W
authors.lastname: Yu
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Xinlong
authors.initials: X
authors.lastname: Xu
authors.forename: Tianlu
authors.initials: T
authors.lastname: Wang
authors.forename: Lixin
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005998:Glycine / Q000378:metabolism; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018782:Maze Learning; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012459:Salicylates / Q000494:pharmacology; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; C435025:N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)-3-(4'-phenylphenoxy)propyl)sarcosine; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018009:Receptors, Glycine; D012459:Salicylates; C493266:Slc6a9 protein, rat; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D005998:Glycine; D012521:Sarcosine