The neuroprotective and hypothermic effect of GYKI-52466, a non-competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-antagonist on histological and behavioural variables in the gerbil global ischemia model

The neuroprotective activity of the non-competitive alpha-amino-3-hydroxy-5 -methyl-4-isoxazolepropionic acid (AMPA) antagonist GYKI-52466 (1-[4-aminop henyl]-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine HCl; EGIS-8159) w as studied in the gerbil bilateral carotid occlusion (BCO) model of global ischemia. Drug effect on hippocampal CA1 neuronal loss, hypermotility, and cognitive deficit (decrease in spontaneous alternation (SA) behaviour in th e Y-maze) induced by 5-min or 3-min BCO were measured. GYKI-52466 was admin istered at 4 x 15 mg/kg intraperitoneal (i.p.) doses 30, 45, 60, and 75 min following surgery. The competitive AMPA antagonist NBQX (2,3-dihidroxy-6-n itro-7-sulfamoyl-benzo(F)-quinoxaline) applied at 3 x 30 mg/kg i.p. doses 6 0, 70, and 85 min after reperfusion was also tested for comparison. Both co mpounds showed weak and non-significant effects on 5-min BCO-induced change s in all the three variables. However, following 3-min ischemia GYKI-52466 and NBQX produced significant inhibition (49% and 48%, respectively) on CA1 cell loss. Moreover, GYKI-52466, but not NBQX, significantly inhibited the 8-min ischemia induced hypermotility and decrease in SA. At their neuropro tective doses, both compounds caused longlasting (min. 8 h) hypothermia in gerbils. GYKI-52466 induced much higher decrease in body temperature (6 deg rees C at peak level) than NBQX did (2 degrees C at peak level). Administra tion of 4 x 10 mg/kg i.p. chlorpromazine to gerbils 15 min before and 0, 15 , and 30 min after 3-min BCO resulted in considerable hypothermia (5.5 degr ees C peak effect, 8 h duration), but no protective action of the compound on CA1 cell loss and hypermotility was observed. However, chlorpromazine in hibited the ischemia-induced cognitive impairment. The results suggest that drug-induced hypothermia may differentially influence the histological and the behavioural outcomes of ischemic intervention. (C) 1999 Elsevier Scien ce Inc.