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Definition of a stroke

A stroke occurs when the normal supply of oxygen to the brain is cut off causing the death of brain cells. The decreased oxygen supply is caused by the interruption of the normal blood flow to the brain, which is normally due to a burst blood vessel or blockage by a clot.

The death of brain cells causes brain damage which affects other bodily functions and can also cause death. The symptoms come on suddenly and can include numbness down one side of the body, dizziness, communication problems and problems swallowing. The symptoms of stroke vary depending on the part of the brain which is damaged.

Incidence

Globally, it is estimated that there are 5.45 million deaths a year from stroke and over 9 million stroke survivors (Rudd, Wolfe, 2002). The highest incidence of stroke is in developed countries; in the UK about 130,000 people suffer a stroke each year. After one year, about a third will be dead and almost 40% of the survivors will be disabled (Kwan, 2001).

Stroke is the second most common cause of death and the most common cause of adult physical disability and the incidence of stroke rises steeply with age. Men have a 25-30% increased likelihood of suffering a stroke compared to women and in the UK African-Caribbean’s and African’s are twice as likely to suffer a stroke as the Caucasian population.

Types of stroke

There are three different types of stroke:

  • Ischaemic
  • Transcient ischaemic attack
  • Haemorrhagic

Ischaemic stroke

Ischaemic stroke accounts for the 85% of all strokes (Rudd, Wolfe, 2002) and can be divided into two forms; thrombotic or embolic. Thrombotic ischaemic stroke occurs when cerebral arteries become blocked by the formation of a blood clot (thrombus) within the brain, and embolic ischaemic stroke occurs when a blood clot that forms elsewhere in the body (usually in the heart) is transported towards the brain via the bloodstream.

Both forms of ischaemic stroke significantly reduce or stop the blood flow to the brain by the formation of blood clots which block the arteries.

Causes of ischaemic stroke

The most common cause of ischaemic stroke is the narrowing of arteries in the head and neck. This is known as atherosclerosis and is caused by the thickening of arteries after the normal lining deteriorates.

Blood cells collect to form a thrombus or an embolism if the arteries become too narrow. Atherosclerosis occurs naturally as a person ages but certain risk factors such as smoking and hypertension can accelerate the process.

Another common cause of ischaemic stroke is atrial fibrillation (irregular heart beat), which can cause the formation of a blood clot. The heart muscle can’t produce enough energy to properly open the heart valve between the atrium and ventricle, which can result in the atrium retaining some of the blood; which increases the risk of blood clots forming in the stagnant blood.

Heart attacks and abnormalities of the heart valves can also cause the formation of blood clots, which can be released into the general circulation and block the carotid arteries causing a stroke. Other less common causes of ischaemic stroke include injury to the blood vessels of the neck and blood abnormalities (polycythemia) and oral contraceptive (increases the risk of clots).

Transient ischaemic attack

Transient ischaemic attack occurs when the blood supply to the brain is temporarily interrupted causing a mini stroke, the obstruction resolves itself through normal mechanisms. The symptoms of a transient ischaemic attack are the same as a stroke but only last a few minutes or hours; however these attacks should be viewed as warning signs that there is a problem with the blood supply to the brain and should not be ignored. There is a 20% chance that a person who has had a transient ischaemic attack will have a proper stroke within four weeks.

Haemorrhagic stroke

Haemorrhagic stroke accounts for 15% of strokes (Rudd, Wolfe, 2002) and occurs when a blood vessel in the brain bursts causing bleeding (haemorrhage) into the brain. There are two different types of haemorrhagic stroke; intercerebral and subarachnoid. Intercerebral haemorrhage is caused when a blood vessel within the brain (usually in the basal ganglia, cerebellum, brainstem or cortex) bursts, allowing blood to leak inside the brain.

Subarachnoid haemorrhage occurs when a blood vessel on the surface of the brain bursts and blood leaks into the subarachnoid space (the space between the brain and the skull). Both types of haemorrhage cause an increased build up of pressure in the brain which leads to the damage of brain cells.

Causes of haemorrhagic stroke

The most common cause of haemorrhagic stroke is hypertension (high blood pressure). Increased blood pressure weakens the arteries it flows through and increases the risk of developing swellings in the arteries (aneurysms), which cause the walls of the blood vessels to weaken and rupture. Other causes of haemorrhagic stroke include traumatic head injuries, tumours, blood vessel abnormalities and blood clotting deficiencies.

Risk factors

Risk factors are factors that increase the chance of a person having a disease or illness and there are many associated with stroke. Some risk factors are modifiable like hypertension, stress, smoking, and obesity, whilst others such as ethnic group, diabetes and heart disease are not. If the risk factors associated with stroke can be modified they can reduce the risk of an individual having a stroke.

  • Hypertension

People who suffer from hypertension have an increased pressure of blood travelling through their blood vessels. This can damage the normal cells lining the inside of the blood vessels causing them to thicken, leading to atherosclerosis. Other risk factors affect hypertension such as smoking, obesity, alcohol consumption, stress and ethnic origin.

  • Stress

Stress is when the mental and physical well being of a person is affected by environmental stimuli. In response to stress the body releases hormones like adrenaline which produce changes in heart rate, blood pressure and metabolism. These changes can cause hypertension and weight gain, which can lead to a stroke.

  • Smoking

Cigarettes contain nicotine which narrows the blood vessels and increases blood pressure causing the heart to beat faster. Smoking can also cause cancer and heart disease, which can both lead to stroke. Fortunately, it is a modifiable risk factor which if stopped can reduce the chances of having a stroke.

  • Obesity

This is a modifiable risk factors often caused by a poor diet and little exercise. Obese people have excess body weight that puts stress on other parts of the body, particularly the circulatory system. Obesity causes hypertension, high cholesterol levels and increases the risk of developing heart disease, diabetes, or stroke.

  • Ethnic group

People of African or Caribbean origin have an increased risk of suffering a stroke because they have a natural tendency to develop heart disease and diabetes, which are two conditions that can cause a stroke. The tendency to develop these conditions may be because African and Caribbean people are more likely to have high blood pressure than people of Caucasian origin. The explanation for this is that African or Caribbean people have an increased sensitivity to the effects of salt, which causes their blood pressure to rise.

  • Diabetes mellitus

Diabetes is a condition characterised by elevated glucose (sugar) levels in the blood. It is caused because the body is unable to produce insulin (type 1) or can produce insulin but it does not function properly (type 2). People who have diabetes are at a much greater risk of having a stroke or developing damaged blood vessels and heart disease than the general population. However, careful monitoring and control of blood sugar levels can reduce the risk.

  • Heart disease

There are different types of heart diseases, some which are non-modifiable like congenital heart disorders and other which are modifiable such as coronary artery disease. Unfortunately, family history of heart disease can’t be modified and is in itself a risk factor.

Heart disease can cause blood clots which have the potential to cause stroke by travelling in the circulation and blocking an artery which supplies the brain with blood. Risk factors such as smoking, diabetes and obesity increase the risk of developing heart disease.

Pathology of ischaemic stroke

Damage to the endothelial cells lining the blood vessels causes circulating monocytes to adhere to the cells and enter the subendothelial space by squeezing through the tight junctions of the endothelial cells. They then transform into macrophages and ingest modified lipids, taking on a foamy appearance.

It is though that macrophages release toxic products that promote platelet adhesion. Growth factors released by platelets stimulate the migration and proliferation of smooth muscle cells which make up a substantial bulk of atherosclerotic lesion. Plaques are extremely vulnerable to fissure because they are composed of lipids that do not have an internal lattice of collagen supporting the cap.

Rupture of the atherosclerotic plaque leads to the activation of the coagulation cascade by exposing the subendothelial collagen to platelets in the bloodstream. The platelets then become activated with cell adhesion, secretion of platelet contents, platelet aggregation and their activated surface is essential for several coagulation reactions that generate thrombin.

Thrombin then converts fibrinogen into fibrin, which forms a blood clot by the aggregating together and trapping platelets, erythrocytes and leukocytes. The clot then contracts, pulling together he edges of the injured surface.

If the clot remains where it is formed it is called a thrombus and if formed in a cerebral artery can cause a stroke by obstructing the blood flow to the brain. However, a small clot (embolism) can break off from a thrombus and travel in the bloodstream until it reaches an artery that is too narrow. It will then obstruct the artery, preventing the blood supply to the brain causing a stroke.

Cellular injury and necrotic cell death

A series of cellular metabolic events (neurotoxicity, inflammation, cell death and angiogenesis), occur rapidly after the interruption of the blood supply to a region of the brain, causing cellular injury and cell death. Necrotic cell death is caused by mechanical injury of the cell or exposure to toxic chemicals. The duration, severity, and location of cerebral ischaemia determine the extent of brain damage.

Brain cells are mainly neurons which transmit and receive nerve impulses in the form of action potentials. The generation of an action potential relies on the difference between the neurons intracellular and extracellular ion concentration, and maintaining these concentration gradients requires a constant supply of oxygen and glucose via the bloodstream.

The cessation of blood supply to an area of cerebral tissue, causes hypoxia and glucose deficiency. Neurons in the ischaemic tissue begin to lose potassium and adenosine triphosphate (ATP), due to the surrounding membrane becoming leaky. It takes between 5-10 minutes of complete arterial occlusion to cause irreversible cerebral damage because the neuronal cells can tolerate the loss of ATP for several minutes.

Energy failure following hypoxia leads to the deterioration of ion concentration gradients and when the intracellular and extracellular ion gradients reach equilibrium, potassium (K+) ions leave the cell and sodium (Na+), and calcium (Ca2+) ions enter the cell. N-methyl-D-aspartate (NMDA) and kainite receptors are highly permeable to these ions, and their activation stimulates the release of excessive amounts of glutamate from the pre-synaptic terminals of the affected neurons.

Glutamate release depolarises the neuronal membrane by allowing the excess influx of Na+and Ca2+. This results in neuronal death because of the swelling of neuronal bodies (caused by Na+) and the activation of Ca2+ dependent effector proteins and enzymes that may cause damage to DNA, lipids and proteins (Mitsios et al, 2006).

There are two major zones of injury following ischaemia; the core ischaemic zone and the ischaemic penumbra. The area of severe ischaemia is the core zone which results in the necrosis of neurons, and the surrounding penumbra is moderately ischaemic tissue between the core zone and normal tissue.

The cells of the penumbra may still be viable for several hours due to the blood supplied by collateral arteries, however if reperfusion is not established within hours these cells will also die. Swelling of the brain can cause further cell death because the cranium doesn’t allow for much room, this increases intercranial pressure. The pressure increase can cause the brain to shift and damage other neurons by compressing them.

Apoptotic cell death

Apoptosis is programmed cell death which makes the cell shrink and collapse inwards causing little damage to surrounding cells. Apoptosis usually occurs when a cell detects DNA damage that can not be repaired. The degeneration and death of neurons in stroke involves apoptotic biochemical cascades and implicates upstream receptors.

P53

P53 is a transcription factor expressed by cells following the detection of DNA damage. It’s responsible is to prevent the replication of damaged DNA by stopping cell division and allowing the damaged DNA to be repaired. However, p53 induced by hypoxia causes apoptosis by increasing the release of cytochrome c, which breaks down the mitochondria.

P53 increases cytochrome c levels by binding to anti-apoptotic proteins preventing them from suppressing cytochrome c release and elevating the levels of proteins that mediate the release of cytochrome c. Increased p53 immunostaining has been observed in neurons and glia following focal cerebral ischaemia in rats (Li Y et al, 1994).

However other findings have indicated that p53 is not a marker of neuronal death following cerebral ischaemia since it rapid and transient induction in the rat hippocampus following global ischaemia was correlated with cell survival. (Tomasevic G et al, 1999)

JNK

JNK are members of the MAPK family and regulate cell death, so providing both protection from apoptosis and apoptosis itself. They are activated by phosphorylation via external stimuli such as cytokines. Only the phosphorylated form of JNK is translocated to the nucleus and has the ability to activate c-jun (Gupta et al 1995). Neuronal death n cerebral ischaemia is due largely to excitotoxic mechanisms which are known to activate the JNK pathway (Gupta et al 1995).

A key role has been confirmed for p-JNK in apoptotic cell death and demonstrated p-JNK co localisation in the nucleus of TUNEL-positive cells with the morphological appearance of neurons from infarct and penumbra of stroke patients (Mitsios et al, 2006). This evidence suggests that JNK activity plays a destructive role in neuronal death following ischaemia and the inhibition of JNK by a JNK inhibitory peptide has resulted in permanent protection against ischaemia in experimental animal models (Borsello et al, 2003).

Inflammation response to ischaemic injury

The inflammatory response in the injured brain is triggered via the reduction of cerebral blood flow after a stroke. Inflammation begins with the expression of inflammatory genes, which leads to release of cytokines, chemokines, and cell adhesion molecules and also involves inflammatory mediators and leukocytes, which exacerbates tissue damage for several days after the onset of symptoms (Mitsios et al, 2006).

Inflammatory mediators

Inflammatory mediators are soluble, diffusible molecules that are released by immune cells. They act both locally at the site of tissue injury and at more distant sites.

  • Arachidonic Acid metabolites

High calcium concentrations which accumulate in brain cells after energy failure activate phospholipase A2 (PLA2) which hydrolyses glycerophospholipids to release arachidonic acid (AA). Following transient middle cerebral artery occlusion (MCAO), PLA2 activity significantly increased (Adibhatla et al., 2006).

As potent mediators, AA metabolites contribute to post-ischemic brain inflammation (Sanchez-Moreno et al, 2004). Consistent with a damaging role of this pathway, PLA2 deficient mice had smaller infarcts and developed less brain edema with fewer neurological deficits than their wild type littermates (Bonventre et al, 1997).

  • Matrix metalloproteinases

Matrix metalloproteinases (MMP’s) are proteases that can break down extracellular proteins such as collagen. They are involved in extracellular matrix remodelling as well as the neuroinflammatory response. MMP’s are normally found in cytosol and are cleaved to their active state by proteases (Rosenberg, 2002). Microglia are a major source of MMP’s following ischaemia and are also needed to stimulate astrocytes to generate active MMP’s (Rosenberg et al., 2001).

After recombinant tissue plasminogen activator (tPA) treatment, components of the blood brain barrier were disrupted following MMP-9 activation (Kelly et al., 2006), and in experimental stroke models, MMP inhibition reduced infarct size, brain edema and hemorrhage (Pfefferkorn and Rosenberg, 2003).

MMP’s seem to participate in plasticity and recovery in the later phases of cerebral ischemia. For instance, MMPs are known to associate with factors involved in angiogenesis such as vascular endothelial growth factor (VEGF). In one study, treatment with an MMP inhibitor after middle cerebral artery occlusion suppressed neurovascular remodelling, increased ischemic brain injury and impaired functional recovery at 14 days (Zhao et al., 2006).

  • Nitric Oxide/Nitric Oxide Synthase

Nitric oxide (NO) is a gas which readily diffuses into cells and cell membranes where it reacts with molecular targets. It is an important signalling molecule involved in physiological processes such as neuronal communication, host defence, and regulation of vascular tone.

Three nitric oxide synthase (NOS) isoforms exist; endothelial NOS, neuronal NOS, and inducible NOS. Inducible NOS (iNOS) is especially relevant to inflammatory cells and may contribute to ischemic injury via NO. Inducible NOS is only expressed by cells involved in inflammatory responses such as circulating leukocytes, microglia and astrocytes.

It was noticed that in the brain, ischemia-induced upregulation of iNOS mRNA and protein is associated with increases in iNOS enzymatic activity and NO production (Iadecola et al., 1995a; Iadecola et al., 1995b). It is also possible that NO may cause DNA damage in cerebral ischemia through the formation of peroxynitrite (Cui et al., 2000; Cui et al., 1999; Huang et al., 2000a). When iNOS was inhibited the infarct volume reduced by about 30% (Iadecola et al., 1995b).

  • Reactive Oxygen Species

Generation of reactive oxygen species (ROS) by inflammatory cells occurs via several enzyme systems. Among all the oxidants in the brain parenchyma after middle cerebral artery occlusion, superoxide anion is a major one, causing direct injury to ischemic brain or by reacting with NO to generate peroxynitrite (Chan, 2001).

NADPH oxidase 2 has cytosolic subunits which translocate to the membrane where they transfer electrons from NADPH to oxygen to form superoxide. Experiments have shown that mice deficient in the gp91 subunit of NOX2 have smaller infarcts than wild type mice (Walder et al., 1997) and recent work has shown that microglia potentiate injury to the blood brain barrier due to superoxide produced by NOX2 in brain ischemia models (Yenari et al., 2006).

Myeloperoxidase (MPO) is an enzyme in leukocytes and has been documented in both permanent and transient middle cerebral artery occlusion (Garau et al., 2005). However, after focal cerebral ischemia, infarct size was increased in MPO deficient mice (Takizawa et al., 2002), suggesting a beneficial role.

MPO deficient mice also had increased products of nitrosylation within the ischemic brain and suggested that MPO‘s protective effect may be due to its ability to scavenge nitrotyrosine (a by product of peroxynitrite reactions) in the presence of glutathione (Takizawa et al., 2002). Therefore, it is possible that MPO may actually limit the extent of ROS-mediated tissue injury.

  • Cytokines

Cytokines are small proteins which are secreted by most cell types in response to infection or trauma. Cytokines are responsible for interacting with various cells of the immune system in order to orchestrate the immune response. Increased numbers of cytokines are found in the brain after a stroke and there are two key cytokines, interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) that are responsible for initiating the inflammatory response, following cerebral ischaemia.

A secondary response follows which involves interleukin-6 (IL-6) and interleukin-8 (IL-8), working with other inflammatory metabolites to activate leukocyte migration to the region of tissue injury. Are also produced by macrophages and t-cells at the site of developing infarction to promote the migration of leucocytes from the vascular lumen into the brain tissue and regulate inflammatory and immune responses.

IL-1 beta is a proinflammatory cytokine that influences the inflammatory cascade by inducing chemotactic cytokines, prostaglandin, collagenase, phosphlipase and other inflammatory cytokines. An experiment has shown that after transient cerebral ischaemia in rats IL-1 beta is expressed in a two phase pattern.

Elevated IL-1 beta mRNA levels and protein expression have been observed an hour after ischaemia and also at later times between six to twenty-four hours (Haqqani et al., 2005). It has been suggested that IL-1 beta plays a destructive role in the pathogenesis of ischaemic brain injury, and an experiment involving the administration of IL-1 beta to rats (Yamasaki et al., 1995) supports this suggestion because increased brain damage occurred.

TNF-α is found in high levels in the brain after ischaemia and in response to ischaemic injury it results in the emigration and infiltration of leukocytes to the injured site. Expression of TNF-α was observed in neurons, microglia and some astrocytes (Liu et al., 1994; Uno et al., 1997). TNF- α has a two phase expression pattern, the initial increase is between 1 to 3 hours (Liu et al., 1994) and the second peaks between 24 to 36 hours (Murakami et al., 2005; Offner et al., 2006).

Subsequently, the inhibition of TNF- α reduces ischaemic brain injury (Yang et al., 1998) by reducing leukocytes infiltration. However, TNF- α may also protect the brain under certain circumstances as it appears to be involved in ischaemic tolerance (Ginis et al., 2002) and mice deficient in TNF receptors have larger infarcts (Bruce et al., 1996).

Interleukin 6 demonstrates both proinflammatory (Benveniste, 1992; Gauldie et al, 1990; Rothwell et al, 1991) and anti-inflammatory effects (Xing et al., 1998). IL-6 plays an important role in the induction of acute phase reactants such as C-reactive protein and fibrinogen. The expression of IL-6 has been observed as early as three hours after ischaemic injury and has lasted up to ninety-six hours in animal models.

Plasma and cerebrospinal fluid levels of IL-6 have been directly correlated with infarct volume and severity of patient outcome (Tarkowski et al, 1995; Fassbender et al. 1994). However, IL-6 deficient mice have similar sized infarcts compared to wild type suggesting that it does not participate in ischemic pathogenesis (Clark et al., 2000)

Interleukin-8 is produced by monocytes, fibroblasts and endothelial cells. It promotes leukocyte binding and also activates neutrophils to generate oxygen free radicals and causes increased endothelial permeability resulting in tissue injury. An increased expression of IL-8 mRNA was found in neutrophils from stroke patients within the first week after the onset of symptoms. (Kostulas et al, 1998).

This suggests an early and sustained mechanism to induce leukocyte activation. A reduction in infarct size has been noted in a rabbit cerebral ischaemia models using an antibody directed against IL-8, also suggesting a crucial role of the chemotactic response in injury after acute ischaemia. (Matsumoto et al, 1997).

  • Chemokines

Chemokines are a family of small proteins which act through specific and shared receptors belonging to the superfamily of G-protein coupled receptors (Bajetto et al., 2001). Chemokines are cytokines that are responsible for chemotactic responses which involves regulating the migration of leukocytes in inflammatory and immune responses.

Expression of chemokines following focal ischemia is thought to have a deleterious role by increasing leukocyte infiltration (Emsley and Tyrrell, 2002), and consistent with a deleterious role, their inhibition or deficiency is associated with reduced injury (Garau et al., 2005).

Monocyte chemoattractant protein-1 (MCP-1) aswell as other chemokines is induced in animal models of focal cerebral ischaemia (Chen et al., 2003). It has also been suggested that MCP-1 may have a role in opening the blood brain barrier (Stamatovic et al., 2005), following a 17 fold permeability increase in an experiment which added MCP-1 to a blood brain barrier model.

Fractalkine is expressed by neurons and after ischaemia can be found on the infarct perimeter and some endothelial cells. It is thought that fractalkine is involved in neuron-microglial signalling because its receptor was observed only on microglial/macrophages (Tarozzo et al., 2002). It is thought that fractalkine exacerbates cell death because fractalkine deficient mice have smaller infarct sizes and lower mortality after transient focal cerebral ischemia (Soriano et al., 2002).

Cell adhesion molecules

Adhesion molecules affect the outcome of stroke by assisting leukocytes infiltration into the ischaemic brain, where they cause further injury to ischaemic tissue. Leukocyte migration happens via three major steps; adhesion, rolling and transendothelial migration.

Adhesion molecules are responsible for mediating the interaction between leukocytes and the endothelium, and there are three groups of adhesion molecules involved in this process; selectins, integrins and the immunoglobulin superfamily.

  • Immunoglobulin superfamily

The immunoglobulin superfamily is a group of proteins that carry out roles in the immune system and are mainly involved with cell surface recognition events. There are five members of the immunoglobulin superfamily: ICAM-1 and ICAM-2, VCAM-1, platelet-endothelial cell adhesion molecule-1 (PECAM-1), and the mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1). However, ICAM-1 and VCAM-1 are the most investigated in cerebral ischaemia.

ICAM-1 exists in low levels on the cell membranes of endothelial cells, epithelial cells, leukocytes and fibroblasts. ICAM-1 expression is increased by cytokine stimulation and precedes leukocyte infiltration. It is increased in the ischemic brain within hours after stroke onset and peaks between 12–24 hours (Wang and Feuerstein, 1995).

Several studies have now shown that blocking ICAM-1 with antibodies (Bowes et al, 1993) or inhibiting ICAM-1 mRNA with antisense oligonucleotides (Vemuganti et al., 2004) improves the outcome of experimental stroke. Experiments have also shown that mice deficient in ICAM-1 have smaller infarcts compared to wildtype mice (Connolly et al, 1996).

Increases in VCAM-1 mRNA after cerebral ischemia have been observed (Blann et al., 1999). VCAM-1 expression has been observed in autopsied brains of stroke victims within cerebral vessels and astrocytes (Blann et al., 1999). However, others have failed to observe such significant changes (Vemuganti et al., 2004), which makes the role of VCAM-1 unclear.

In a study of global cerebral ischemia in rats, a potent leukotriene receptor antagonist (ONO-1078), reduced neuron death and improved neurological deficits by inhibiting the upregulation of VCAM-1 in the hippocampus of ischemic rats (Zhang and Wei, 2003). However, another study suggested that VCAM-1 may not play an important role in ischaemic brain injury because treatment with anti-VCAM-1 antibodies did not have any effect on the outcome of stroke (Justicia et al., 2006).

  • Integrins

Integrins are receptor proteins that are involved in cell-cell interactions and cell-extracellular matrix interactions. They are extremely important as they allow cells to bind and respond to the extracellular matrix. Integrins consist of a β subunit and a variable α subunit (Albelda, 1991). There are three subfamilies for the β subunits. Those involved in the structure of the extracellular matrix and bind laminin, collagen and fibronectin are β1 integrins. β2 integrins are involved in leukocyte cell adhesion and β3 integrins are factors involved in the production of clots.

β2 integrins on the surface of leukocytes recognise endothelial cell adhesion molecules, allowing leukocytes to adhere to the endothelium, following activation by chemoattractants (Smith, 1993). CD11b is a β2 integrin and is the most studied integrin in stroke models.

In an in vitro study, hypoxia caused an increase of neutrophil CD11b expression compared to normoxia, and this injury was protected by aprotinin by reducing the upregulation of neutrophil CD11b (Harmon et al., 2004). Blocking CD11b and CD18 reduces injury from experimental stroke and is associated with decreased neutrophil infiltration (Jiang et al., 1995). Similarly, mice lacking CD18 exhibited reduced leukocyte adhesion to endothelial cell monolayers, and improved cerebral blood flow and less neurological injury and neutrophil accumulation when subjected to experimental stroke (Prestigiacomo et al., 1999).

  • Selectins

Integrins are a family of transmembrane glycoproteins which are expressed on the cell surface of leukocytes and endothelial cells after activation by histamine or thrombin. There are three different kinds of selectins; E-selectin, P-selectin and L-selectin (Carlos and Harlan, 1994). E-selectin and P-selectin are involved in leukocyte rolling (allows the leukocytes to roll along the endothelial surface) and recruitment during the early stages of activation, and L-selectin acts as a guide for unstimulated leukocytes (Bargatze et al., 1994).

L-selectin is expressed on most leukocytes and contributes to the initial interaction between leukocytes and endothelium during evolving inflammation. mediates leukocyte transmigration; however an experiment which involved treating rabbits exposed to transient focal brain ischemia with an L-selectin antibody (Yenari et al., 2001) showed no affect on stroke outcome.

P-selectin is stored in the granules of platelets and endothelial cells and are expressed on the cell surface within minutes after stimulation. The expression of P-selectins have been documented in different experimental stroke models and their upregulation appears to be involved in promoting ischemic inflammatory responses and increases injury due to ischemic stroke (Huang et al., 2000b).

In animal studies, mice overexpressing P-selectin had exacerbation of infarcts, whereas treatment with antibodies or inhibitors against P- and E-selectin was associated with improved neurological outcome (Huang et al, 2000).

Other animal studies showed that neutrophils accumulated in the ischemic cortex of wildtype mice more abundantly than in P-selectin knockout mice in focal cerebral ischaemia (Connolly et al., 1997) and P-selectin deficient mice had smaller infarct volumes and improved survival compared with the wildtype mice.

E-selectin expressed on endothelial cells is upregulated, and peaks within 4-8 hours of injury. Recent work has shown that exposing animals to E-selectin can reduce the extent of injury by inducing immune tolerance to brain antigens (Chen et al., 2003). E-selectin tolerance prevents leukocyte trafficking into the brain, which is very important and could possibly lead to the development of a vaccine against stroke.

Inflammatory cells

There are many different types of inflammatory cells and following brain ischaemia inflammatory cells such as leukocytes, microglia and astrocytes are activated and accumulate in the brain tissue causing inflammatory injury.

  • Astrocytes

An astrocyte is a small, glial cell that surrounds nerve cells and play important roles in neuron maintenance and function. However, activated astrocytes have the potential to pose harm to ischemic brain; they express inflammatory mediators and express different kinds of mediators to other inflammatory cells (Benveniste, 1998).

They are activated after brain ischaemia, which results in increased glial fibrillary acidic protein expression (Pekny and Nilsson, 2005). Astrocytes can secrete inflammatory factors such as cytokines, chemokines and inducible nitric oxide synthase (iNOS) (Dong and Benveniste, 2001).

Inducible nitric oxide synthase in astrocytes has been shown to potentiate ischemia-like injury to neurons (Hewett et al., 1996), and expression was found in reactive astrocytes of hippocampus after ten minutes of transient global ischaemia, but not in uninjured hippocampal astrocytes (Endoh et al., 1994). Astrocytes also produce tumour necrosis factor-like weak inducer of apoptosis (TWEAK) which is a member of the tumour necrosis factor superfamily (Donohue et al., 2003).

  • Microglia/Macrophages

Microglia, are the resident macrophages of the brain and serve as scavenger cells in the event of infection, inflammation, trauma, ischemia, and neurodegeneration (El Khoury et al., 1998). It is thought that cerebral ischaemia induces microglial activation transforming them into phagocytes that are virtually indistinguishable from circulating macrophages. In transient MCAO, phagocytic microglial were documented in the cerebral cortex of the ischemic hemisphere (Zhang et al., 1997).

Microglial activation causes the release of a variety of substances many of which are cytotoxic and/or cytoprotective (Wood, 1995). A tetracycline family antibiotic (minocycline), was shown to provide significant protection against brain ischemia by inhibiting microglial activation and proliferation (Yrjanheikki et al., 1998). Direct evidence supporting a damaging role after ischemic insults were demonstrated when microglia/macrophages were applied to neuron cultures and injury from various ischemia-like insults was increased (Zhang et al., 1997).

  • Leukocytes

There are several sub-types of leukocytes but only two of real importance in the inflammation response following stroke are neutrophils and lymphocytes. Between four to six hours after ischemia onset, circulating leukocytes adhere to vessel walls, leading to migration and accumulation into ischemic brain tissue with subsequent release of proinflammatory mediators. These mediators lead to secondary injury of potentially salvageable tissue within the ischaemic penumbra surrounding the infarct core.

Neutrophils are the first leukocyte subtype recruited to the ischemic brain, and may potentiate injury by directly secreting deleterious substances or other inflammatory mediators (Hallenbeck, 1996). In transient ischemia, several studies have shown that infarct volume is significantly reduced when neutrophil infiltration is inhibited (Bowes et al, 1995;) and numerous studies have seen improved neurological outcomes following neutrophil depletion and inhibition of adhesion molecules which help neutrophils enter into the injured brain (Zheng and Yenari, 2004).

Lymphocytes were thought to play a negative role in ischemic brain pathogenesis, because preventing lymphocyte transport into the ischemic brain reduced injury, which suggested that like neutrophils, lymphocytes also play a deleterious role (Becker et al, 2001).

Following permanent middle cerebral artery occlusion in rats, lymphocytes were elevated in the ischemic lesion after neutrophils (Li et al, 2005). However, in a study of cultured primary neurons, isolated neutrophils, but not lymphocytes potentiate neuronal injury due to excitotoxin exposure (Dinkel et al, 2004).

Transcriptional regulation of inflammation

Cerebral ischaemia upregulates gene expression and the activation of several transcription factors have been observed in experimental stroke models. The following signal transduction pathways and transcription factors are involved in the inflammation response after a stroke:

  • Mitogen-activated protein kinase (MAPK)

Signal transduction pathways allow cells to receive external signals and respond in an appropriate manner. The MAPK signalling pathways play an important role in transducing stress-related signals. There are three MAPK signal transducing pathways; the stress-activated protein kinases/c-Jun N-terminal kinases (SAPK/JNK), the p38 MAPKs and extracellular signal-regulated kinases (ERKs) (Irving and Bamford, 2002; Irving et al, 2000; Sugino et al, 2000).

These pathways operate through sequential phosphorylation events to phosphorylate transcription factors and regulate inflammatory gene production. The p38 MAPK promotes the stabilization and enhanced translation of mRNAs encoding proinflammatory proteins (Kyriakis and Avruch, 2001).

In permanent middle cerebral artery occlusion, a major neuronal membrane lipid precursor, showed a key role in recovery after ischaemic stroke by a notable reduction in the phosphorylation of MAP-kinase family members. Also, p38 MAPK inhibitors have been shown to reduce brain injury and neurological deficits in focal cerebral ischemia as well as ischemia-induced cytokine expression (Barone and Feuerstein, 1999).

  • Nuclear factor kappa B (NF-κ B)

NF-κB proteins are dimeric and comprise a family of transcription factors that are involved in the regulation of inflammation (Baeuerle and Henkel, 1994). NF-κB is located in the cytoplasm of most cells in its inactive state, bound to its endogenous inhibitor protein (IκB). As with the NF-κB proteins there are a family of IκB proteins. IκB protein is responsible for primarily regulating NF-κB.

When a cell starts to receives large numbers of extracellular signals, the NF-κB is released from its inhibitor by an IκB kinase (IKK). The inhibition of IKK activity reduced infarct size in a mouse model of stroke and the activation of IKK2 enlarged the infarct size (Herrmann et al., 2005).

After being released, the NF-κB protein then enters the nucleus where it binds to a 9-10 base pair DNA site, known as a κB site, where it activates gene expression. Many genes that are involved in inflammation contain functional κB sites, such as tumour necrosis factor-α. It has been discovered that mice deficient in NF-κB’s p50 subunit are protected from experimental stroke (Schneider et al., 1999).

  • Activator Protein-1 (AP-1)

AP-1 is a family of dimeric transcription factors composed of FOS, JUN or ATF (activating transcription factor) subunits, which all bind to the same DNA site (the AP-1 binding site). The upstream activation of AP-1 components is mediated through the JNK/SAPK cascade.

The association of FOS and JUN proteins is required for DNA binding and involves the use of a leucine zipper, which is provided by the FOS oncoprotein. The hydrophobic interactions between leucines are responsible for holding the transcription factor together. AP-1 regulates the expression of a number of target genes by binding to the AP-1 DNA site.

The stimulation of cells with different stimuli induces c-Fos transcription and c-Fos was found to be up regulated as early as 30 minutes after stroke onset (Lu et al, 2004). Also the decrease of c-fos and c-jun mRNA and AP-1 DNA binding by lipopolysaccharide (LPS) caused by the inhibition of p38 MAP kinase, subsequently led to neuroprotection in cerebral ischemia (Simi et al, 2000).

Angiogenesis

Breaking up the clot (thrombolysis) occluding the artery is a very effective method for achieving early reperfusion in patients, however this is only done on a small number of patients because of the time limitations.

Angiogenesis is the formation of new blood vessels and is crucial for the restoration of blood flow to potentially viable tissue (penumbra). The stimulation of angiogenesis by hypoxia is thought to result from the inhibition of hypoxia-inducible factor-1 degradation. This would allow the expression and activation of vascular endothelial growth factor (VEGF), which promotes angiogenesis.

VEGF is secreted by macrophages, leucocytes and damaged blood platelets involved with the inflammation response. Increased VEGF expression was reported in human brain tissue following acute ischaemic stroke (151). Thrombolysis and angiogenesis are extremely important factors that affect the recovery of the patient.

If blood supply can be restored in time brain cells in the penumbra can be saved which will reduce further brain damage and provide a better outcome for the patient. Angiogenesis within the penumbra of the damaged brain region occurred after the onset of ischaemic stroke in man and the extent of angiogenesis was correlated with a patient’s survival time (Krupinski et al, 1994).

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