The neuroprotective activity of the non-competitive
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (
AMPA) antagonist
GYKI-52466 (1-[4-aminophenyl]-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodia zep ine HCI; EGIS-8159) was 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 the Y-maze) induced by 5-min or 3-min BCO were measured.
GYKI-52466 was administered 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-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline) applied at 3 x 30 mg/kg i.p. doses 60, 70, and 85 min after reperfusion was also tested for comparison. Both compounds showed weak and non-significant effects on 5-min BCO-induced changes 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 3-min
ischemia induced hypermotility and decrease in SA. At their neuroprotective doses, both compounds caused long-lasting (min. 8 h)
hypothermia in gerbils.
GYKI-52466 induced much higher decrease in body temperature (6 degrees C at peak level) than
NBQX did (2 degrees C at peak level). Administration 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 degrees C peak effect, 8 h duration), but no protective action of the compound on CA1 cell loss and hypermotility was observed. However,
chlorpromazine inhibited the
ischemia-induced
cognitive impairment. The results suggest that
drug-
induced hypothermia may differentially influence the histological and the behavioural outcomes of ischemic intervention.