Animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s of ischemic stroke are procedures inducing

cerebral ischemia Brain ischemia is a condition in which there is insufficient bloodflow to the brain to meet metabolic demand. This leads to poor oxygen supply in the brain and may be temporary such as in transient ischemic attack or permanent in which there is ...

. The aim is the study of basic processes or potential therapeutic interventions in this disease, and the extension of the pathophysiological knowledge on and/or the improvement of medical treatment of human ischemic stroke. Ischemic stroke has a complex

pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...

involving the interplay of many different cells and tissues such as

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

glia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...

endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...

, and the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

. These events cannot be mimicked satisfactorily

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

yet. Thus a large portion of stroke research is conducted on animals.

Overview

Several models in different species are currently known to produce cerebral ischemia. 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

gerbils Gerbillinae is one of the subfamilies of the rodent family Muridae and includes the gerbils, jirds, and sand rats. Once known as desert rats, the subfamily includes about 110 species of African, Indian, and Asian rodents, including sand rats an ...

. They do not have a

Circle of Willis The circle of Willis (also called Willis' circle, loop of Willis, cerebral arterial circle, and Willis polygon) is a circulatory anastomosis that supplies blood to the brain and surrounding structures in reptiles, birds and mammals, including huma ...

and stroke can be induced by common carotid artery occlusion alone.

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 : * Endothelin-1 -induced constriction of arteries and veins *

Middle cerebral artery The middle cerebral artery (MCA) is one of the three major paired cerebral artery, cerebral arteries that supply blood to the cerebrum. The MCA arises from the internal carotid artery and continues into the lateral sulcus where it then branches an ...

occlusion (MCAO) ** MCAO avoiding

craniotomy A craniotomy is a surgery, surgical operation in which a bone flap is temporarily removed from the Human skull, skull to access the Human brain, brain. Craniotomies are often critical operations, performed on patients who are suffering from brain ...

*** 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 * 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

. 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

(MCA) occlusion is achieved in this model by injecting particles like blood clots (thrombembolic MCAO) or artificial spheres into the carotid artery of animals as an animal model of ischemic stroke. Thrombembolic MCAO is achieved either by injecting clots that were formed in vitro or by endovascular instillation of

thrombin Prothrombin (coagulation factor II) is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...

for in situ clotting . The thrombembolic model is closest to the pathophysiology of human cardioembolic stroke. When injecting spheres into the cerebral circulation, their size determines the pattern of brain infarction: Macrospheres (300–400 μm) induce infarcts similar to those achieved by occlusion of the proximal MCA , whereas microsphere (~ 50 μm) injection results in distal, diffuse embolism . However, the quality of MCAO – and thus the volume of brain

infarct Infarction is tissue death (necrosis) due to inadequate blood supply to the affected area. It may be caused by artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as an infarct (from the ...

s – is very variable, a fact which is further aggravated by a certain rate of spontaneous

lysis Lysis ( ; from Greek 'loosening') is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ...

of injected blood clots.

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 . It is applied to rats and mice. A piece of surgical filament is introduced into the

internal carotid artery The internal carotid artery is an artery in the neck which supplies the anterior cerebral artery, anterior and middle cerebral artery, middle cerebral circulation. In human anatomy, the internal and external carotid artery, external carotid ari ...

and forwarded until the tip occludes the origin of the

middle cerebral artery The middle cerebral artery (MCA) is one of the three major paired cerebral artery, cerebral arteries that supply blood to the cerebrum. The MCA arises from the internal carotid artery and continues into the lateral sulcus where it then branches an ...

, resulting in a cessation of blood flow and subsequent brain

infarction Infarction is tissue death (necrosis) due to Ischemia, inadequate blood supply to the affected area. It may be caused by Thrombosis, artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as a ...

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) who described filament introduction via the

external carotid artery The external carotid artery is the major artery of the head and upper neck. It arises from the common carotid artery. It terminates by splitting into the superficial temporal and maxillary artery within the parotid gland. Structure Origin T ...

, allowing closure of the access point with preserved blood supply via the

common Common may refer to: As an Irish surname, it is anglicised from Irish Gaelic surname Ó Comáin. Places * Common, a townland in County Tyrone, Northern Ireland * Boston Common, a central public park in Boston, Massachusetts * Cambridge Com ...

and internal carotid artery to the brain after the removal of the filament. Known pitfalls of this method are insufficient occlusion,

subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid (brain), arachnoid membrane and the pia mater surrounding the human brain, brain. Symptoms may include a thunderclap headache, severe heada ...

hyperthermia Hyperthermia, also known as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme te ...

, and

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...

of the ipsilateral extracranial tissue . Filament MCAO is not applicable to all rat strains .

Permanent transcranial middle cerebral artery occlusion

In this animal model of ischemic stroke the

(MCA) is surgically dissected and subsequently permanently occluded, e.g. by

electrocautery Cauterization (or cauterisation, or cautery) is a medical practice or technique of burning a part of a body to remove or close off a part of it. It destroys some tissue in an attempt to mitigate bleeding and damage, remove an undesired growth, o ...

ligation Ligation may refer to: * Ligation (molecular biology), the covalent linking of two ends of DNA or RNA molecules * Chemical ligation, the chemoselective condensation of unprotected peptides * In medicine, the making of a ligature (tie) * Tubal liga ...

. Occlusion can be performed on the proximal or distal part of the MCA. In the latter, ischemic damage is restricted to the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

. MCAO can be combined with temporal or permanent

common carotid artery In anatomy, the left and right common carotid arteries (carotids) () are artery, arteries that supply the head and neck with oxygenated blood; they divide in the neck to form the external carotid artery, external and internal carotid artery, inte ...

occlusion. These models require a small

Transient transcranial middle cerebral artery occlusion

The technique of modeling

ischemic stroke Stroke is a medical condition in which poor blood flow to a part of the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop ...

by transient transcranial MCAO is similar to that of permanent transcranial MCAO, with the MCA being reperfused after a defined period of focal cerebral ischemia . Like permanent MCAO, craniotomy is required and

(CCA) occlusion can be combined. Occluding one MCA and both CCAs is referred to as the three vessel occlusion model of focal cerebral ischemia.

Cerebrocortical photothrombosis

Photothrombotic models of ischemic stroke use local intravascular photocoagulation of circumscribed cortical areas. After intravenous injection of photosensitive dyes like rose-bengal, the brain is irradiated through the skull via a small hole or a thinned cranial window, leading to photochemical occlusion of the irradiated vessels with secondary tissue ischemia . This approach was initially proposed by Rosenblum and El-Sabban in 1977, and improved by Watson in 1985 in the rat brain. This method has also been adapted for use in mice.

References

* * * * * * * * * * * * * * * *

References

{{reflist Ischemia

Ischemic stroke Stroke is a medical condition in which poor blood flow to a part of the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop ...

Stroke

Overview

Mechanisms of inducing ischemic stroke

Hypoxic Ischemia models

Focal ischemia models

Endothelin-1 -induced constriction of arteries and veins

Embolic middle cerebral artery occlusion

Endovascular filament middle cerebral artery occlusion

Permanent transcranial middle cerebral artery occlusion

Transient transcranial middle cerebral artery occlusion

Cerebrocortical photothrombosis

See also

References

References