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Neuroprotection in human ischaemic stroke is possible. Discuss whether this hypothesis has been adequately tested
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Grace Laporta U1839904BS374 Modern Approaches to Human disease
Question 3 Neuroprotection in human ischaemic stroke is possible. Discuss whether this
hypothesis has been adequately tested
Introduction
Most strokes 80-85% are Ischemic, caused by a local obstruction thrombus or embolus, a blood clot
that travels through the bloodstream to the brain, both interrupt the blood supply to the brain.
disrupting the supply of oxygen and nutrients to the brain, causing damage to the tissue. Stroke has
a significant socioeconomic impact worldwide (1) being the second leading cause of death and the
third leading cause of disability globally (2). Furthermore, because of demographic changes and
insufficient control of major risk factors for stroke, the number of patients with stroke will rise in the
future (3). The development of clinically effective neuroprotective drugs to reduce the severity of
brain injury and improve outcomes following a stroke is a high priority and an unmet need.
Neuroprotective drugs given at the time of first contact with the patient have the potential to extend
the therapeutic time window for these interventions such as thrombectomy, while reducing tissue
damage and the risk of haemorrhagic and oedema related complications (4). The goal for
neuroprotection is based on the concept of preserving the penumbra.
Action of Adenosine
When a stroke occurs, there is ATP depletion as the brain isn’t supplied oxygen through the blood,
giving rise to adenosine which is released during metabolic stress and activity. Making a rat brain
tissue ischemic by depriving it of oxygen and glucose, leads to an increase in adenosine which is
associated with the inhibition of glutamatergic synaptic transmission. Adenosine is an antagonist so
inhibits the A1 receptor on the postsynaptic neuron, hyperpolarising the neurons. Which intensifies
the Mg2+ blocking the NMDA receptors reducing electrical activity in the brain and demand for ATP
when there is a low blood supply.
An infusion of the specific adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine
(DPCPX) was given to the sheep before asphyxia was induced for 10 mins mimicking a stroke (5).
After asphyxia, EEG strength in control foetuses gradually returned to baseline values within 6 to 8
hours. In comparison, all DPCPX-treated foetuses developed delayed-onset seizures which are
clinical markers for asphyxia damage (6). These seizures were characterised by stereotypic high-
voltage/low-frequency function, increased nuchal muscle activity, heart rate and blood pressure.
There was also a significant increase in the neuronal loss within the Cornu Ammonis hippocampal
regions, parasagittal cortex, and striatum in the DPCPX group (P<0.01; Figure 1 a-b). This evidence
shows blocking adenosine results in greater cerebral damage characterised by severe clinical
seizures and greater neuronal loss.
Figure 1 Images and quantification of
neuronal loss in DPCPX and control
conditions a) photomicrographs of the
striatum and CA1 region of the
Hippocampus. The DPCPX treated foetuses
show cell death in the striatum and CA1
region indicated by the arrows whereas in
control-treated animals this is not observed.
b) The quantification of neuronal loss in
different regions of the brain in DPCPX-
treated and control foetuses. Values are
shown as means ±SEM. *P<0.01 DPCPX vs
control foetuses. (Hunter, C.J et al 2003)
, Grace Laporta U1839904
BS374 Modern Approaches to Human disease
This shows extreme asphyxia in the foetal lamb, rapid suppression of neuronal activity is not due to
profound tissue anoxia but is actively mediated by adenosine release. The activation of the
adenosine A1 receptor in the near-term foetus during extreme asphyxia offers essential defence
against neuronal injury.
Adenosine has therapeutic potential
Although adenosine has therapeutic potential because of its rapid metabolization and clearance
from the bloodstream, it’s ineffective when given systemically (7). To overcome these limitations,
researchers developed an injectable neuroprotection formulation by combining adenosine with
squalene (SQAd) (8). This was injected into mice 2hrs before the induction of ischaemia. In the SQAd
treated mice the infarct volume was significantly decreased (24 ± 4 mm3) compared with the
vehicle-treated control group (54 ± 3 mm3) (Fig 2a). There were also improvements in neurologic
deficit scores coinciding with reductions in infarct size (Fig 2b)
Figure 2 a Reduced Nissl staining under a light microscope identifying ischemic volumes in control and treated mice
subjected to transient and permanent cerebral ischaemia (Values are mean ±SEM N = 6 animals per group; † and * indicate
P= 0.05). In comparison to control groups that received vehicle, SQAd nano-assemblies (7.5/15mg kg1) or adenosine (5.5mg
kg1), intravenous administration just before ischaemia or 2 hrs post-ischemia significantly decreased the infarct volume. b
SQAd nano-assemblies also had a significant therapeutic effect when given 2 hrs after ischemia. SQAd also had a
neuroprotective effect significantly reducing neurologic deficit scores 24 hrs after the induction of stroke. (Gaudin, A 2004)
This demonstrates that SQAd nano-assemblies allows for the efficient administration of this
adenosine with substantial pharmacological activity which Is neuroprotective within an ischaemia
brain model.
NMDA as a therapeutic target in rats
Another therapeutic target is NMDA receptors, coupled to a molecule called PSD-95 associated with
the enzyme neuronal nitric oxide synthase which is over-activated during ischemic conditions
resulting in nitrous oxide which is toxic at high concentrations (9). Therefore, by reducing activation
of neuronal nitric oxide synthase the production of nitric oxide is decreased reducing the amount of
cell death associated with over activation of the NMDA receptor. A single intravenous injection in
saline of postsynaptic density-95 inhibitors was given to the rats (Tat-NR2B9c[SDV] or Tat-
NR2B9c(ADA) an inactive control) 1 or 3 hours after a stroke (10). Treatment with Tat-NR2B9c(ADA)
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