Animal model of ischemic stroke
Overview
Several models in different species are currently known to produce cerebral ischemia[1]. Global ischemia models, both complete and incomplete, tend to be easier to perform. However, they are less immediately relevant to human stroke than the focal stroke models, because global ischemia is not a common feature of human stroke. However, in various settings global ischemia is also relevant, e.g. in global anoxic brain damage due to cardiac arrest. Different species also vary in their susceptibility to the various types of ischemic insults. An example is
Mechanisms of inducing ischemic stroke
Some of the mechanisms which have been used are:
- Complete global ischemia
- Decapitation
- Aorta/vena cava occlusion
- External neck tourniquet or cuff
- Cardiac arrest
- Incomplete global ischemia
- Hemorrhage or hypotension
- Hypoxic ischemia
- Intracranial hypertension and common carotid artery occlusion
- Two-vessel occlusion and hypotension
- Four-vessel occlusion
- Unilateral common carotid artery occlusion (in some species only)
- Focal cerebral ischemia
- Endothelin-1-induced constriction of arteries and veins
- Middle cerebral artery occlusion
- Spontaneous brain infarction (in spontaneously hypertensive rats)
- Macrosphere embolization
- Multifocal cerebral ischemia
- Blood clot embolization
- Microsphere embolization
- Photothrombosis
Hypoxic Ischemia models
One of the most commonly used animal models of hypoxic ischemia was originally described by Levine in 1960 and later refined by Rice et al., in 1981. This approach is useful to study hypoxic ischemia in the developing brain, since newborn rat pups are utilized in this model. Briefly, 7 day old rat pups undergo a permanent unilateral carotid artery ligation with a subsequent 3 hour exposure to a hypoxic environment (8% oxygen). This model creates a unilateral infarct in the hemisphere ipsilateral to the ligation, since the hypoxia alone is subthreshold for injury at this age. The area of injury is typically concentrated in periventricular regions of the brain, especially cortical and hippocampal areas.
Focal ischemia models
They are divided into techniques including reperfusion of the ischemic tissue (transient focal cerebral ischemia) and those without reperfusion (permanent focal cerebral ischemia). The following models are established [2]:
- Endothelin-1 -induced constriction of arteries and veins
- Middle cerebral artery occlusion (MCAO)
- MCAO avoiding craniotomy
- Embolic middle cerebral artery occlusion
- Endovascular filament middle cerebral artery occlusion (transient or permanent)
- MCAO involving craniotomy
- Permanent transcranial middle cerebral artery occlusion
- Transient transcranial middle cerebral artery occlusion
- MCAO avoiding craniotomy
- Direct tissue damage
- Cerebrocortical photothrombosis
Endothelin-1 -induced constriction of arteries and veins
Endothelin-1 is a potent vasoconstrictor which is produced endogenously during ischemic stroke and which contributes to overall loss of cells and disability. Exogenous endothelin-1 can also be used to induce stroke and cell death after sustained vasoconstriction with reperfusion. It can be microinjected to induce focal stroke in small tissue volumes (e.g., cortical grey matter, white matter or subcortical tissue) or after injection near the Middle cerebral artery. It is often used as a model of focal stroke to evaluate candidate pro-regenerative therapies. One advantage of this model of stroke is that it causes highly reproducible infarcts. Another benefit is that it can be used in elderly rats with only very low resulting mortality.
Embolic middle cerebral artery occlusion
Endovascular filament middle cerebral artery occlusion
The technique of endovascular filament (intraluminal suture) MCAO as an animal model of ischemic stroke was described first by Koizumi [7]. It is applied to rats and mice. A piece of surgical filament is introduced into the internal carotid artery and forwarded until the tip occludes the origin of the middle cerebral artery, resulting in a cessation of blood flow and subsequent brain infarction in its area of supply. If the suture is removed after a certain interval, reperfusion is achieved (transient MCAO); if the filament is left in place the procedure is suitable as model of permanent MCAO, too. The most common modification is based on Longa (1989) [8] who described filament introduction via the external carotid artery, allowing closure of the access point with preserved blood supply via the common and internal carotid artery to the brain after the removal of the filament. Known pitfalls of this method are insufficient occlusion, subarachnoid hemorrhage [9], hyperthermia [10], and necrosis of the ipsilateral extracranial tissue [11]. Filament MCAO is not applicable to all rat strains [12].
Permanent transcranial middle cerebral artery occlusion
In this animal model of ischemic stroke the
Transient transcranial middle cerebral artery occlusion
The technique of modeling
Cerebrocortical photothrombosis
Photothrombotic models of ischemic stroke use local intravascular photocoagulation of circumscribed cortical areas. After intravenous injection of photosensitive dyes like
See also
- animal models of stroke
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