Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.

Excessive activation of the N-methyl-D-aspartic acid (NMDA) type glutamate receptors (NMDARs) causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca(2+)]i influx are potential leads for development to treat excitotoxicity-induced br...

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Autores principales:	Zhao Han, Jin-Long Yang, Susan X Jiang, Sheng-Tao Hou, Rong-Yuan Zheng
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/21941edbb8b844a9943fe382a1c2020d
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spelling	oai:doaj.org-article:21941edbb8b844a9943fe382a1c2020d2021-11-18T07:43:31ZFast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.1932-620310.1371/journal.pone.0064894https://doaj.org/article/21941edbb8b844a9943fe382a1c2020d2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23741413/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Excessive activation of the N-methyl-D-aspartic acid (NMDA) type glutamate receptors (NMDARs) causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca(2+)]i influx are potential leads for development to treat excitotoxicity-induced brain damage. Our previous studies showed that 2-(2-benzofu-ranyl)-2-imidazoline (2-BFI), an immidazoline receptor ligand, dose-dependently protects rodent brains from cerebral ischemia injury. However, the molecular mechanisms remain unclear. In this study, we found that 2-BFI transiently and reversibly inhibits NMDA, but not AMPA currents, in a dose-dependent manner in cultured rat cortical neurons. The mechanism of 2-BFI inhibition of NMDAR is through a noncompetitive fashion with a faster on (Kon = 2.19±0.33×10(-9) M(-1) sec(-1)) and off rate (Koff = 0.67±0.02 sec(-1)) than those of memantine, a gold standard for therapeutic inhibition NMDAR-induced excitotoxicity. 2-BFI also transiently and reversibly blocked NMDA receptor-mediated calcium entry to cultured neurons and provided long-term neuroprotection against NMDA toxicity in vitro. Collectively, these studies demonstrated a potential mechanism of 2-BFI-mediated neuroprotection and indicated that 2-BFI is an excellent candidate for repositioning as a drug for stroke treatment.Zhao HanJin-Long YangSusan X JiangSheng-Tao HouRong-Yuan ZhengPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e64894 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zhao Han Jin-Long Yang Susan X Jiang Sheng-Tao Hou Rong-Yuan Zheng Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.
description	Excessive activation of the N-methyl-D-aspartic acid (NMDA) type glutamate receptors (NMDARs) causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca(2+)]i influx are potential leads for development to treat excitotoxicity-induced brain damage. Our previous studies showed that 2-(2-benzofu-ranyl)-2-imidazoline (2-BFI), an immidazoline receptor ligand, dose-dependently protects rodent brains from cerebral ischemia injury. However, the molecular mechanisms remain unclear. In this study, we found that 2-BFI transiently and reversibly inhibits NMDA, but not AMPA currents, in a dose-dependent manner in cultured rat cortical neurons. The mechanism of 2-BFI inhibition of NMDAR is through a noncompetitive fashion with a faster on (Kon = 2.19±0.33×10(-9) M(-1) sec(-1)) and off rate (Koff = 0.67±0.02 sec(-1)) than those of memantine, a gold standard for therapeutic inhibition NMDAR-induced excitotoxicity. 2-BFI also transiently and reversibly blocked NMDA receptor-mediated calcium entry to cultured neurons and provided long-term neuroprotection against NMDA toxicity in vitro. Collectively, these studies demonstrated a potential mechanism of 2-BFI-mediated neuroprotection and indicated that 2-BFI is an excellent candidate for repositioning as a drug for stroke treatment.
format	article
author	Zhao Han Jin-Long Yang Susan X Jiang Sheng-Tao Hou Rong-Yuan Zheng
author_facet	Zhao Han Jin-Long Yang Susan X Jiang Sheng-Tao Hou Rong-Yuan Zheng
author_sort	Zhao Han
title	Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.
title_short	Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.
title_full	Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.
title_fullStr	Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.
title_full_unstemmed	Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.
title_sort	fast, non-competitive and reversible inhibition of nmda-activated currents by 2-bfi confers neuroprotection.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/21941edbb8b844a9943fe382a1c2020d
work_keys_str_mv	AT zhaohan fastnoncompetitiveandreversibleinhibitionofnmdaactivatedcurrentsby2bficonfersneuroprotection AT jinlongyang fastnoncompetitiveandreversibleinhibitionofnmdaactivatedcurrentsby2bficonfersneuroprotection AT susanxjiang fastnoncompetitiveandreversibleinhibitionofnmdaactivatedcurrentsby2bficonfersneuroprotection AT shengtaohou fastnoncompetitiveandreversibleinhibitionofnmdaactivatedcurrentsby2bficonfersneuroprotection AT rongyuanzheng fastnoncompetitiveandreversibleinhibitionofnmdaactivatedcurrentsby2bficonfersneuroprotection
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Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection.

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