Cell-permeant Ca2+
chelators such as 1,2-bis-(2-aminophenoxy)ethane- N,N,N',N'-tetraacetic
acid acetoxymethyl
ester (
BAPTA-AM) have been reported to protect neurons in experimental focal
cerebral ischemia. However, their in vivo actions are uncertain, and their protective efficacy is proven only in brief
cerebral ischemia paradigms. Here we examine their mechanism of action in vitro and duration of efficacy in vivo. Electrophysiological studies were made in CA1 neurons in rat hippocampal slices. When superfused with
BAPTA-AM (30-50 microM), CA1 somatic field potential recordings showed attenuation of the population spike amplitude, and intracellular recordings showed reduced excitatory postsynaptic potentials, indicating inhibition of excitatory synaptic transmission. Also, Ca(2+)-dependent accommodation and post-spike-train hyperpolarizations were reduced, indicating Ca2+ chelation hear the internal cell membrane surface. To determine whether Ca2+
chelators reduce the size of
cerebral infarction rather than simply delaying its evolution, we studied the effects of
BAPTA-AM treatment on
infarction size 24 h after permanent
middle cerebral artery occlusion. Fischer rats (n = 8 per group) were pretreated with saline,
BAPTA-AM (20 mg/kg), or
MK-801 (0.5 mg/kg).
Infarction volumes in animals treated with
BAPTA-AM were reduced by 50.5% compared with controls (p = 0.018), whereas animals treated with
MK-801 experienced a statistically insignificant
infarct volume reduction (26%; p = 0.27). These data show a persistence of neuroprotection by the Ca2+
chelator at 24 h and indicate that it may act by attenuating synaptic transmission and subplasma membrane Ca2+ excess.