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Protection by imidazol(ine) drugs and agmatine of glutamate‐induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor
Author(s) -
Olmos Gabriel,
DeGregorioRocasolano Nuria,
Regalado M Paz,
Gasull Teresa,
Boronat M Assumpció,
Trullas Ramón,
Villarroel Alvaro,
Lerma Juan,
GarcíaSevilla Jesús A
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702679
Subject(s) - nmda receptor , agmatine , glutamate receptor , pharmacology , neurotoxicity , cerebellum , neuroscience , blockade , chemistry , metabotropic glutamate receptor 6 , metabotropic glutamate receptor 1 , metabotropic glutamate receptor , granule (geology) , receptor , biology , biochemistry , toxicity , organic chemistry , amino acid , arginine , paleontology
This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate‐induced necrosis and on apoptosis induced by low extracellular K + in cultured cerebellar granule cells. Exposure (30 min) of energy deprived cells to L ‐glutamate (1–100 μ M ) caused a concentration‐dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L ‐glutamate‐induced neurotoxicity (EC 50 =5 μ M ) was blocked by the specific NMDA receptor antagonist MK‐801 (dizocilpine). Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 μ M (EC 100 ) L ‐glutamate with the rank order (EC 50 in μ M ): antazoline (13)>cirazoline (44)>LSL 61122 [2‐styryl‐2‐imidazoline] (54)>LSL 60101 [2‐(2‐benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2‐(1,4‐benzodioxan‐6‐yl)‐4,5‐dihydroimidazole] (101)>RX821002 (2‐methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K + ) which does not involve stimulation of NMDA receptors. Imidazol(ine) drugs and agmatine fully inhibited [ 3 H]‐(+)‐MK‐801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L ‐glutamate neurotoxicity correlated well ( r =0.90) with the potency of the same compounds competing against [ 3 H]‐(+)‐MK‐801 binding. In HEK‐293 cells transfected to express the NR1‐1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage‐ and concentration‐dependent block of glutamate‐induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC 50 of 10–12 μ M at 0 mV. It is concluded that imidazol(ine) drugs and agmatine are neuroprotective against glutamate‐induced necrotic neuronal cell death in vitro and that this effect is mediated through NMDA receptor blockade by interacting with a site located within the NMDA channel pore.British Journal of Pharmacology (1999) 127 , 1317–1326; doi: 10.1038/sj.bjp.0702679