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Volume 17, Number 10,
Issue of May 15, 1997
pp. 3538-3553
Copyright ©1997 Society for Neuroscience
Mechanisms and Effects of Intracellular Calcium Buffering on
Neuronal Survival in Organotypic Hippocampal Cultures Exposed to
Anoxia/Aglycemia or to Excitotoxins
Received Dec. 10, 1996; revised Feb. 18, 1997; accepted Feb. 25, 1997.
Khaled M. Abdel-Hamid1 and
Michael Tymianski1, 2
1 Playfair Neuroscience Unit and 2 Division
of Neurosurgery, University of Toronto, Toronto, Ontario M5T-2S8,
Canada
Neuronal calcium loading attributable to hypoxic/ischemic injury is
believed to trigger neurotoxicity. We examined in organotypic hippocampal slice cultures whether artificially and reversibly enhancing the Ca2+ buffering capacity of neurons reduces
the neurotoxic sequelae of oxygen-glucose deprivation (OGD), whether
such manipulation has neurotoxic potential, and whether the mechanism
underlying these effects is pre- or postsynaptic. Neurodegeneration
caused over 24 hr by 60 min of OGD was triggered largely by NMDA
receptor activation and was attenuated temporarily by pretreating the
slices with cell-permeant Ca2+ buffers such as 1,2 bis(2-aminophenoxy)ethane-N,N,N ,N-tetra-acetic acid
acetoxymethyl ester (BAPTA-AM). This pretreatment produced a transient,
reversible increase in intracellular buffer content as demonstrated
autoradiographically using slices loaded with 14C-BAPTA-AM
and by confocal imaging of slices loaded with the BAPTA-AM analog
calcium green-acetoxymethyl ester (AM). The time courses of
14C-BAPTA retention and of neuronal survival after OGD were
identical, indicating that increased buffer content is necessary for
the observed protective effect. Protection by Ca2+
buffering originated presynaptically because BAPTA-AM was ineffective when endogenous transmitter release was bypassed by directly applying NMDA to the cultures, and because pretreatment with the low
Ca2+ affinity buffer
2-aminophenol-N,N,O-triacetic acid acetoxymethyl ester,
which attenuates excitatory transmitter release, attenuated neurodegeneration. Thus, in cultured hippocampal slices, enhancing neuronal Ca2+ buffering unequivocally attenuates or delays
the onset of anoxic neurodegeneration, likely by attenuating the
synaptic release of endogenous excitatory neurotransmitters
(excitotoxicity).
Key words:
calcium;
cell death;
anoxia;
calcium buffers;
neurotoxicity;
organotypic cultures;
hippocampal neurons;
BAPTA;
oxygen-glucose deprivation;
presynaptic mechanisms
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