The Journal of Neuroscience, July 1, 1998, 18(13):4891-4900
Upregulation of the Enzyme Chain Hydrolyzing Extracellular ATP
after Transient Forebrain Ischemia in the Rat
Norbert
Braun1,
Yuan
Zhu2,
Josef
Krieglstein2,
Carsten
Culmsee2, and
Herbert
Zimmermann1
1 Biozentrum der J.W. Goethe-Universität, AK
Neurochemie, D-60439 Frankfurt am Main, Germany, and
2 Institut für Pharmakologie und Toxikologie,
Phillips-Universität, D-35032 Marburg, Germany
A short ischemic period induced by the transient occlusion of major
brain arteries induces neuronal damage in selectively vulnerable
regions of the hippocampus. Adenosine is considered to be one of the
major neuroprotective substances produced in the ischemic brain. It can
be released from damaged cells, but it also could be generated
extracellularly from released ATP via a surface-located enzyme chain.
Using the rat model of global forebrain ischemia, we applied a short
(10 min) transient interruption of blood flow and studied the
distribution of ectonucleotidase activities in the hippocampus.
Northern hybridization of mRNA isolated from hippocampi of
sham-operated and ischemic animals revealed an upregulation of
ectoapyrase (capable of hydrolyzing nucleoside 5'-tri- and
diphosphates) and ecto-5'-nucleotidase (capable of hydrolyzing
nucleoside 5'-monophosphates). A histochemical analysis that used ATP,
UTP, ADP, or AMP as substrates revealed a strong and selective increase
in enzyme activity in the injured areas of the hippocampus. Enhanced
staining could be observed first at 2 d. Staining increased within
the next days and persisted at 28 d after ischemia. The
spatiotemporal development of catalytic activities was identical for
all substrates. It was most pronounced in the CA1 subfield and also
could be detected in the dentate hilus and to a marginal extent in CA3.
The histochemical staining corresponded closely to the development of
markers for reactive glia, in particular of microglia. The upregulation
of ectonucleotidase activities implies increased nucleotide release
from the damaged tissue and could play a role in the postischemic
control of nucleotide-mediated cellular responses.
Key words:
astrocyte; ectoapyrase; ecto-ATPase; ecto-5'-nucleotidase; ischemia; microglia
Copyright © 1998 Society for Neuroscience 0270-6474/98/18134891-10$05.00/0