Focal cerebral ischemia due to occlusion of
a major cerebral artery is the cause of
ischemic stroke which is a major reason of
mortality, morbidity and disability in the
populations of the developed countries. In
the seven studies summarized in the thesis
focal ischemia in rats induced by occlusion
of the middle cerebral artery (MCAO) was
used as an experimental model of ischemic
stroke. MCAO produces an acute lesion
consisting of an ischemic core or focus with
severely reduced blood flow surrounded by
a borderzone or ischemic penumbra with
less pronounced blood flow reduction. Cells
in the ischemic focus are irreversibly
damaged after only 15-30 minutes of
ischemia. In contrast, cells in the penumbra
may – although threatened and functionally
impaired – remain viable for several hours
following arterial occlusion but will
eventually also succumb if ischemia persists.
In this way the initially viable tissue in the
penumbra is recruited in the infarction
process leading to a progressive growth of
the infarct. The penumbra hence constitutes
an important target for pharmacological
treatment because of the existence of a
therapeutic time window during which
treatment with neuroprotective compounds
may prevent recruitment of penumbra to
infarct resulting in mitigation of the final
ischemic brain damage.
The pathogenetic mechanisms involved in
ischemic cell death in the penumbra
encompass excitotoxic mechanisms
mediated by activation of ionotropic
glutamate receptors, loss of cellular calcium
homeostasis and accelerated generation of
damaging free oxygen radiacals.
The overall aim of the studies was to
elucidate the pathogenetic and pathophysiological
mechanisms involved in
recruitment of the penumbra in the acute
phase of focal ischemia. In the three first
studies, it was specifically addressed how
the glutamate receptor antagonsists MK-801
and NBQX influence expression of Fos
protein, a product of the immediate-early
gene c-fos, and changes of general protein
synthesis and glucose consumption in the
penumbra in the acute phase following
MCAO. The effect of treatment with
ketobemidone, an opioid receptor agonist
and weak NMDA glutamate receptor
antagonist, upon protein synthesis and
glucose metabolism in the penumbra and
infarct volume was investigated in a fourth
study. In the fifth study, transient periinfarct
depolarizations were recorded and the effect
of treatment with the free radical scavenger
α-PBN on the periinfarct depolarizations
and infarct volume was investigated. In
study number six, the activity of the
mitochondrial electron transport complexes
I, II and IV was evaluated histochemically
during reperfusion after MCAO in order to
assess the possible role of mitochondrial
dysfunction in focal ischemic brain damage.
Finally, the effect on infarct volume one
week after MCAO of treatment with
Pinokalant, a new broad-spectrum cation
channel blocker, was examined in the
seventh study.
The results of these studies are presented
and discussed in relation to the current
knowledge of the pathogenetic and pathophysological
mechanisms involved in the
acute phase of the infarction process.