Salvageable brain

The concept of the ischemic penumbra has proven to be an extremely valuable construct for both experimental studies of ischemic stroke and for the development of tools for the management of patients with this disorder. Indeed, a major driver in the development of treatments for ischemic stroke is the belief that in many acute stroke patients, there is a region of salvageable brain that is threatened with permanent injury. This region of brain corresponds to the ischemic penumbra originally described in experimental stroke studies. The clinical condition does not strictly meet the criteria as originally defined by experimentalists. Nonetheless, the concept is clinically valuable, and a suitable modification of its definition applicable to the clinical condition is appropriate. 

Liver, the major site of purine nucleotide biosynthesis, provides purines and purine nucleosides for salvage and utilization by tissues incapable of their biosynthesis. For example, human brain has a low level of PRPP amidotransferase (reaction 2, Figure 34-2) and hence depends in part on exogenous purines. Erythrocytes and polymorphonuclear leukocytes cannot synthesize 5-phosphoribosylamine (strucmre III, Figure 34-2)... 

Junghans U, Seitz RJ, Ritzl A, Wittsack HJ, Fink GR, Freund HJ, Siebler M. Ischemic brain tissue salvaged from infarction by the GP Ilb/IIIa platelet antagonist tirofiban. Neurology 2002 58 474- 76. 

In many cells, the capacity for de novo synthesis to supply purines and pyrimidines is insufficient, and the salvage pathway is essential for adequate nucleotide synthesis. In patients with Lesch-Nyhan disease, an enzyme for purine salvage (hypoxanthine guanine phosphoribosyl pyrophosphate transferase, HPRT) is absent. People with this genetic deficiency have CNS deterioration, mental retardation, and spastic cerebral palsy associated with compulsive self-mutilation, Cells in the basal ganglia of the brain (fine motor control) normally have very high HPRT activity. These patients also all have hyperuricemia because purines cannot be salvaged. 

De Bow S. B. and Colboume F. (2003) Delayed transient ischemic attacks kill some C A1 neurons previously salvaged with postischemic hypothermia neuroprotection undone. Brain Res. 959, 50-57. 

While the PRTases salvage nucleobases within cells, nucleosides such as adenosine and uridine are present in the blood at much higher concentrations ( 1 pM) than the equivalent nucleobases, adenine and uracil. Indeed, the brain synthesizes pyrimidine nucleotides (UTP and CTP) via salvage synthesis from uridine produced by the liver and released into the circulation. Human cells may contain at least three types of nonspecific nucleoside transporters, and nucleosides are internalized more rapidly than nucleobases. 

The mechanism by which deficiency of HPRT causes central nervous system disorders remains unknown. Lesch-Nyhan patients do not show anatomical abnormalities in the brain. In normal subjects, HPRT activity is high in the brain and, in particular, in the basal ganglia where de novo purine biosynthesis is low. This suggests the importance of the purine salvage pathway in this tissue. However, the relationship between HPRT deficiency and... 

The purine bases are produced de novo by pathways that use amino acids as precursors and produce nucleotides. Most de novo synthesis occurs in the hver (Fig. 41.2), and the nitrogenous bases and nucleosides are then transported to other tissues by red blood cells. The brain also synthesizes significant amounts of nucleotides. Because the de novo pathway requires six high-energy bonds per purine produced, a salvage pathway, which is used by many cell types, can convert free bases and nucleosides to nucleotides. 

Most of the de novo synthesis of the bases of nncleotides occurs in the liver, and to some extent in the brain, neutrophils, and other cells of the immune system. Within the liver, nucleotides can be converted to nucleosides or free bases, which can be transported to other tissues via the red blood cell in the circulation. In addition, the small amounts of dietary bases or nucleosides that are absorbed also enter cells in this form. Thus, most cells can salvage these bases to generate nucleotides for RNA and DNA synthesis. For certain cell types, such as the lymphocytes, the salvage of bases is the major form of nucleotide generation. 

The CTA protocol described in this chapter was designed to provide diagnostically useful information about both the vascular and parenchymal phases of brain enhancement. The administration of contrast serves two purposes first, to visualize acute clot in the MCA, distal internal carotid artery (ICA), basilar artery, and other major circle of Willis vessels (Fig. 4.1) and second, to better delineate potentially salvageable, underperfused, ischemic areas of the brain that are at risk for full infarction if circulation is not restored. More specifically, this includes those areas with a relative lack of contrast enhancement on CTA source images (CTA-Sl). Moreover, CTA-Sl can also be of value in suggesting otherwise unsuspected... 

To summarize the above discussion, the portion of an acute stroke patient s brain that appears normal in DWI images, but underperfused in PWI maps, is generally presumed to represent the ischemic penumbra, i.e., the tissue that is at risk of infarction but still potentially salvageable by reperfusion. This presumption has several implications that can be tested empirically. First, it implies that patients with a large diffusion-perfusion... 

Restoration of cerebral blood flow (CBF) to normal remains the mainstay of acute stroke treatment. The main challenge of acute stroke treatment is timely evaluation and administration of thrombolytic therapy for qualified patients. Animal studies have demonstrated that there is a very short window of opportunity when brain tissue is salvageable if CBF is reinstated. Clinical studies have demonstrated similar... 

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