F. Colbourne et al., Continuing postischemic neuronal death in CA1 - Influence of ischemia duration and cytoprotective doses of NBQX and SNX-111 in rats, STROKE, 30(3), 1999, pp. 662-667
Background and Purpose-Transient forebrain ischemia results in a 24- to 72-
hour delayed loss of CA1 neurons. Previous work has not assessed whether in
sult durations can vary the degree and maturation rate of CA1 injury and wh
ether there are different ultrastructural features of death after brief or
severe ischemia. We also tested whether known cytoprotective drugs achieve
permanent or transient neuroprotection.
Methods-In the first experiment, ischemia was induced for 5, 15, or 30 minu
tes with the use of the 4-vessel occlusion rat model with 1- to 28-day surv
ival. Others subjected to 5 or 15 minutes of ischemia and allowed to surviv
e for 14 or 7 days, respectively, were examined with electron microscopy. F
inally, we determined whether NBQX (30 mg/kg x3 at 0 or 6 hours after ische
mia), an AMPA antagonist, and SNX-111 (5 mg/kg at 6 hours after ischemia),
an N-type Ca2+ channel antagonist, provided enduring CA1 protection against
10 minutes of ischemia.
Results-CA1 damage was not detected at 24 hours. Thirty minutes of ischemia
produced 47% and 84% CA1 damage at 2 and 3 days, respectively. A 15-minute
occlusion yielded 11%, 74%, and 86% loss at 2, 3, and 7 days, respectively
. Five minutes of ischemia produced an even slower progression with 24%, 52
%, and 59% loss at 3, 7, and 14 days, respectively. Ultrastructural examina
tion after 5 and 15 minutes of ischemia revealed necrosis with no morpholog
ical evidence of apoptosis. Both NBQX (P<0.021) and SNX-111 (P<0.001) signi
ficantly reduced CA1 death at 7 days (less than or equal to 35%) but not at
28 days (greater than or equal to 80%) compared with saline treatment (app
roximate to 79%).
Conclusions-Brief forebrain ischemia results in a slower progression of CA1
loss than more severe insults. Nonetheless, neuronal injury had necrotic,
not apoptotic, morphology. NBQX and SNX-111 only postponed CA1 injury.