Biomedical Engineering Reference
In-Depth Information
example to illustrate the potential and also problems associated with imaging approaches in
preclinical DDD: the evaluation of anti-ischemic therapy in models of focal cerebral ischemia.
Stroke is a leading cause of death in industrialized nations and the only clinically approved treat-
ment is thrombolysis using recombinant tissue plasminogen activator (rtPA) applicable in approxi-
mately 5% of stroke patients. Hence, there is a high medical need to develop novel pharmacological
therapies.
Focal cerebral ischemia is caused by transient or permanent occlusion of a major cerebral artery.
Cessation of local perfusion initiates a cascade of detrimental effects within minutes such as energy
failure due to the shutdown of aerobic ATP synthesis that affects all energy-dependent processes of
the cell including membrane pumps required to maintain ion homeostasis, and intracellular signal-
ing cascades via ATP-dependent protein kinases. Failure of membrane pumps causes intracellular
Ca
2+
to accumulate prompting a cascade of deleterious downstream events for the cell ultimately
leading to cell death. Excessive levels of excitatory neurotransmitters such as glutamate are another
major reason for tissue exhaustion and damage as the inactivation of glutamate via glial and neu-
ronal uptake is an energy-dependent process. Elevated glutamate levels cause opening of
N
-methyl-
d-aspartate (NMDA) receptors enhancing Ca
2+
inl ux with the consequences already discussed.
Glutamate interaction with metabotropic glutamate receptors (mGluR) activates second-messenger-
mediated signaling. In addition to these acute effects, delayed infarct growth due to recruitment of
penumbral regions has been observed at time points beyond 48 h after infarction, associated with
apoptosis and neuroinl ammation. Therapeutic strategies in stroke target the individual processes
of the pathophysiological cascade.
Long-term tissue survival can only be achieved through restoration of blood supply to the isch-
emic lesion, which has to occur within a short time frame of a few hours. In the acute phase, protec-
tive effects can be achieved by reducing the energy demand in affected brain areas that show some
residual perfusion (ischemic penumbra). This can be achieved by administration of Ca
2+
channel
blockers, which reduce Ca
2+
inl ux through voltage-gated channels, or by inhibition of receptor-
operated channels such as the NMDA receptor. Both strategies have been rather successful in ani-
mal models of focal cerebral ischemia. A number of other therapeutic targets have been investigated
such as glycine receptors, prevention of excitotoxicity using antagonists of the
-amino-3-hydroxy-
5-methyl-isoxazole-4-propionate (AMPA) receptor, free-radical scavengers, inhibitors of death pro-
tease, or anti-inl ammatory treatment. Yet, all these compounds failed upon translation into the
clinics, mostly due to lack of efi cacy. More recently, tissue repair strategies using neuronal stem or
progenitor cells have been proposed, which revealed benei cial effects in a rat stroke model.
Today, imaging techniques, and in particular MRI-based methods, enable the visualization of
individual aspects of the pathophysiological cascade both in humans and in animals from the initial
vascular occlusion to the ini ltration of inl ammatory cells during the postacute phase. The same
techniques have been applied to evaluate the efi cacy of anti-ischemic drugs.
For example, it has been shown that in models of global ischemia pretreatment with cytoprotec-
tive Ca
2+
inhibitors signii cantly delayed ATP depletion and tissue acidosis. Yet, most of the pre-
clinical stroke studies evaluating drug efi cacy using MRI are based on morphometric readouts, i.e.,
they use infarct volumes as efi cacy biomarker. The underlying assumption is that reduction of the
structural damage, i.e., reduction of the infarct volume, will necessarily translate into an improved
behavioral or correspondingly clinical outcome. The classical MRI method for the assessment of
cerebral infarct volume is based on
R
2
contrast: formation of a vasogenic edema leads to signii -
cantly reduced
R
2
values (and correspondingly increased T
2
= 1/
R
2
values) providing a good demar-
cation between ischemic and intact tissue (Figure 7.5). A considerable number of drug candidates
have been evaluated using this approach. It has to be kept in mind that cerebral tissue displaying a
decreased
R
2
-value is already irreversibly damaged; hence the method indicates an endpoint. Earlier
indicators that provide a signii cant contrast for tissue that is still salvageable are the apparent water
diffusion coefi cients (ADC) in brain parenchyma and local cerebral blood l ow (CBF) rates. It has
been demonstrated, at least in animal models of global and focal ischemia, that ADC changes are
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