Stroke and Inflammation

Ischemic strokes account for around 80-85% of all strokes and are caused by arterial vascular occlusions rarely occlusion in the cerebral venous system may result in ischemic and/or hemorrhagic stroke. Arterial occlusions resulting from cerebral embolism are the most common causes of ischemic strokes, and by about one week after stroke as many as 70-90% of occlusions will have spontaneously recanalized. Emboli typically originate from atherosclerotic stenoses in the internal carotid artery or from sources in the heart such as clots in the left atrium or the left ventricle. Hypertension-induced vascular disease of the small perforating intracerebral arteries is a common cause of lacunar strokes. A classification of the major stroke subtypes is shown in Table 31.1. 

Immediately after the onset of focal brain ischemia, oxygen and glucose deprivation result in loss of adenosine triphosphate (ATP), loss of maintenance of normal ion channels and neuronal depolarization (Wahlgren and Ahmed, 2004) as evidenced by calcium and sodium influx into the cells. 

Ischemic (80-85%) Large artery Carotid artery stenosis 

Stroke-related inflammation in the brain appears to largely result from a selective migration and infiltration of systemic (i.e., circulating) leukocytes to the focus of cerebral ischemia. These cells are predominantly those of the innate immune system, at least initially. Activated neutrophil polymorphs begin to infiltrate as early as 4h after stroke, initially being 

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Han HS, Qiao Y, Karabiyikoglu M, Giffard RG, Yenari MA. Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. J Neurosci 2002 22 3921-3928. 

In addition to their beneficial effects, some medications may actually cause cellular injury and disease. An example of this phenomenon involves nonsteroidal anti-inflammatory drugs (NSAIDS). These drugs include aspirin (a derivative of salicylic acid), ibuprofen (arylpropionic acid, Advil ), and acetaminophen (para-aminophenol derivative, Tylenol ). Because of their beneficial pharmacological effects, consumption of these agents has increased significantly in recent years. NSAIDS have the ability to treat fever, pain, acute inflammation, and chronic inflammatory diseases such as arthritis. They are also used prophylactically to prevent heart disease, stroke, and colon cancer. 

The FDA approved this selective cyclooxigenase (COX)-2 inhibitor (Vioxx) for the treatment of pain and inflammation in 1999. This NSAID demonstrated to have a lower risk of side effects such as gastrointestinal ulcers and bleeding than nonse-lective COX inhibitors, for example, ibuprofen. In 2004, a long-term study of Vioxx in patients at increased risk of colon polyps was halted because of an increased cardiovascular risk (heart attack, stroke) in the rofecoxib group. Subsequently, Merck withdrew the drug from the world market at the end of September 2004 [46]. 

Nonpeptide receptors Adenosine Aj Human cDNA Cardiac arrhythmia, asthma, myocardial ischemia, obesity, pain, renal disease, sleep apnea, stroke, cancer, inflammation, glaucoma, cystic fibrosis, Alzheimer s disease, Parkinson s disease Bradycardia, lipolysis inhibition, reduction of glomerular filtration and natriuresis, tubero-glomerular feedback, antinociception, renal vasodilatation-constriction, reduction of central cholinergic and noradrenergic nerve activity, presynaptic inhibition of excitatory neuro transmission... 

The main differences between necrosis and apoptosis are in the triggers (accidental v. physiological), the process (energy-independent vs. dependent), and the outcomes (with vs. without inflammation). However, apoptosis and/or necrosis can be induced by the same causes in some cases (K16). Alteration of mitochondrial permeability is involved in both apoptosis and necrosis (K16). Both apoptosis and necrosis are found in conditions such as stroke and myocardial infraction (F5), and necrosis can occur secondary to apoptosis (T4). To preserve the usefulness of the two terms for denoting different modes of cell death while still recognizing possible overlap of the two processes (H7), some more descriptive terms have been proposed primary necrosis (oncosis, ischemic cell death) (Ml) and secondary necrosis (apoptotic necrosis, necrosis secondary to apoptosis) (K15). 

Engstrom G, Lind P, Hedblad B, Stavenow L, Janzon L, Lindgarde F. Effects of cholesterol and inflammation-sensitive plasma proteins on incidence of myocardial infarction and stroke in men. Circulation 2002 105 2632-2637. 

Maier C. M., Ahem K., Cheng M. L., Lee J. E., Yenari M. A., and Steinberg G. K. (1998) Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke 29, 2171-2180. 

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