Neurological deficit

Figure 1 Schematic diagram illustrating the key factors involved in microvascular and neuronal secondary injury after TBI or SCI.

metabolism, and the accumulation of lactate. The second is activation of mitochondrial and cytoplasmic nitric oxide synthase (NOS) and nitric oxide (NO) production. The third is activation of phospholipase A2 liberating arachidonic acid (AA), which is then converted by cyclooxygenases (COX-1 and COX-2) to a variety of prostanoids with deleterious actions. These include the potent vasoconstrictor prostaglandin F2a (PGF2a) and the vasoconstrictor/platelet aggregation promoter thromboxane A2 (TXA2). In addition, activated lipoxygenases lead to an increase in tissue leukotrienes (LTs), some of which are chemoattractants for inflammatory polymorphonuclear (PMN) leukocyte and macrophage influx that can invade the injured or ischemic tissue and amplify the secondary injury process. The fourth consequence of intracellular Ca2 + overload is the activation of the calcium-activated protease calpain, which degrades a variety of cellular substrates, including cytoskeletal proteins.

A byproduct of mitochondrial dysfunction, COX and lipoxygenase activity, and NOS activation is the formation of reactive oxygen species (ROS), including peroxynitrite (ONOO-). Peroxynitrite is a product of the reaction of superoxide radical with NO. Although peroxynitrite can trigger cellular damage by a variety of mechanisms, cell membrane (plasma and organellar) lipid peroxidation (LP) has been conclusively demonstrated to be a key mechanism.2'6'7 However, iron is a powerful catalyst that accelerates the propagation of LP reactions. Glycolytically derived lactate promotes LP by stimulating the release of iron from storage sites, (e.g., ferritin). In addition, primary and secondary petechial hemorrhages supply hemoglobin-bound iron. Lipid peroxidation occurs in neurons and blood vessels, directly impairing neuronal and axonal membrane function and integrity, and causing microvascular damage and secondary ischemia that indirectly contributes to the secondary neuronal injury.

For SCI the secondary events occur initially in the central gray matter, spreading to the surrounding white matter. As implied above, the key issue in predicting recovery of function is the degree of preservation of the ascending and descending white matter tracts. Many of the axons that do survive, however, do not conduct impulses due to posttraumatic demyelination. Therefore, the goal of neuroprotective pharmacotherapy in the context of SCI is to preserve as many of the white matter axons and as much of their investing myelin as possible. In TBI a key determinant in neurological recovery is also the loss of axons. Based upon the often widespread loss of axons in the injured brain, this phenomenon is referred to as 'diffuse axonal injury'. However, it should be realized that a significant factor in influencing the extent of neural injury both in TBI and SCI is a decrease in brain or spinal cord microvascular perfusion

(i.e., secondary ischemia). When this occurs, the result is an exacerbation of the injury process due to superimposed tissue ischemic hypoxia. Moreover, deficiencies in CNS hypoperfusion can be aggravated by systemic hypotension and/ or hypoxia. Thus, it is important to note that secondary injury involves both neuronal and microvascular events.

For ischemic stroke, the goal is to limit the extent of the infarction by preventing secondary injury in the partially perfused penumbral region surrounding the core of the infarct. In SAH the main focus of attention has been on finding ways to prevent the delayed vasospasm phenomenon, which leads to secondary ischemic infarction. For intracerebral hemorrhage the hope is that the deleterious effects of the hematoma on the surrounding tissue can be prevented, and edema and ischemic damage limited.

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