Role of Nitric Oxide in Stimuli Induced Changes in the Blood Brain Barrier

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As discussed for the role of nitric oxide in maintaining the basal integrity of the peripheral circulation, the role of nitric oxide in stimuli-induced changes in peripheral microvascular permeability is also controversial. Some have suggested that the generation of nitric oxide inhibits, whereas an increasing number of studies now suggest that the synthesis/release of nitric oxide accounts for increases in permeability of peripheral blood vessels in response to a variety of stimuli. Although the role of nitric oxide in permeability of the peripheral circulation is becoming increasingly clear, the precise role and cellular mechanisms by which nitric oxide may alter the permeability of the blood-brain barrier in response to various stimuli remains uncertain. The following discussion focuses on studies that have begun to implicate a role for nitric oxide in permeability of the blood-brain barrier under several conditions, that is, stimulation with inflammatory mediators, cerebral hypoxia, cerebral ischemia, and bacterial infections.

Inflammatory Mediators/Cytokines

Before a precise role for nitric oxide in stimuli-induced changes in permeability of the blood-brain barrier could be advanced, it was important to determine whether nitric oxide could directly alter the permeability of the blood-brain barrier. Several lines of evidence suggest that nitric oxide can influence the permeability of the blood-brain barrier. Initial studies found that application of a nitric oxide donor, sodium nitroprusside, could reduce electrical resistance across cultured brain endothelium. In addition, application of nitric oxide increased paracellular permeability of isolated cerebral endothelium. Further, studies from our laboratory have shown that application of donors of nitric oxide (Sin-1 and SNAP) to the cerebral microcirculation produced an increase in permeability of the blood-brain barrier. Thus, it appears that nitric oxide has the ability to produce an increase in the permeability of the blood-brain barrier.

Over the past several years, it has become apparent that many cerebrovascular diseases have an inflammatory component. Since nitric oxide has been shown to contribute to changes in peripheral vascular permeability in response to inflammatory mediators, a number of studies have begun to examine the contribution of nitric oxide to changes in permeability of the blood-brain barrier during stimulation with inflammatory mediators/cytokines. Unfortunately, few studies have examined the precise role of the various isoforms of nitric oxide in this process. For example, it has been difficult to examine the precise role of eNOS in the permeability of the blood-brain barrier since there are no specific inhibitors of eNOS. Thus, most studies that have attempted to implicate a role of eNOS in stimuli-induced changes in permeability of the blood-brain barrier have used a rationale similar to that used for studies of cerebrovascular reactivity, that is, the use of nonspecific inhibitors of NOS (L-NAME, L-NMMA, and L-NNA). Using this experimental regimen, we and others have suggested that the synthesis/release of nitric oxide, presumably via activation of eNOS, contributes to increases in permeability of the blood-brain barrier, primarily in cerebral venules and veins, in response to several important inflammatory mediators (i.e., histamine, bradykinin) that may be released during brain trauma and during acute arterial hypertension.

Cytokines are a group of polypeptides that are involved in the activation of the immune system and in the inflammatory response. Cytokines are classified into several categories including interleukins, tumor necrosis factors, chemokines, interferons, growth factors, and neurotrophins. Cytokines are synthesized/released by many cell types within the brain (microglia, astrocytes, endothelial cells, macrophages, and T-cells) and may play a crucial role in the development of inflammation in the brain during cerebrovascular diseases. For example, there is an increase in the levels of interleukins and tumor necrosis factor in the cerebrospinal fluid of human subjects following acute stroke, subarachnoid hemorrhage, cerebral ischemia, or traumatic brain injury. In addition, neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and AIDS-related dementia also appear to have an inflammatory component in their pathology that may be related to the synthesis/release of cytokines. Thus, although a number of studies have shown that cytokines can produce dramatic changes in the permeability of the blood-brain barrier, only recently has the role of nitric oxide in this process been acknowledged. However, the precise role of nitric oxide, the contribution of the various cellular sources of nitric oxide, and potential mechanisms by which nitric oxide can alter the permeability of the blood-brain barrier during pathophysiologic conditions remain unknown.

Cerebral Hypoxia

A number of metabolic changes to the brain can influence reactivity of cerebral blood vessels, regulation of cerebral blood flow, and perhaps the permeability of the blood-brain barrier. Hypoxia produces dramatic increases in the diameter of cerebral blood vessels that appears to be related, in part, to the synthesis/release of nitric oxide, presumably via the activation of nNOS. However, the effects of hypoxia on the blood-brain barrier are controversial. Some investigators have shown that hypoxia produces an increase in permeability of the blood-brain barrier that can be inhibited by exogenous generation of nitric oxide. In contrast, others have shown that hypoxia-induced changes in permeability of the blood-brain barrier can be markedly reduced by inhibition of eNOS or iNOS. Further, others have shown that hypoxia-induced alterations in permeability of the blood-brain barrier are related to changes in the expression of tight-junctional proteins between adjacent endothelial cells. Thus, future studies will be required to precisely examine the role of nitric oxide, the cellular source of nitric oxide, and the influence of nitric oxide on pathways that account for changes in permeability of the blood-brain barrier during hypoxia.

Cerebral Ischemia

Cerebral ischemia has dramatic effects on the nitric oxide biosynthetic pathway. NOS-dependent reactivity of cerebral arteries is impaired following cerebral ischemia/reperfusion via a mechanism that appears to be related to the inactiva-tion of nitric oxide by oxygen radicals. In addition, studies have shown that nitric oxide concentration in the ischemic area increases within several minutes during cerebral ischemia. This increase in nitric oxide production appears to involve activation of eNOS and nNOS during the onset of ischemia, and iNOS during the progression of cerebral ischemia. Although there is little debate regarding the effects of cerebral ischemia on reactivity of cerebral blood vessels and the production of nitric oxide, there is considerable debate regarding the role nitric oxide plays in the mechanisms of ischemic brain injury. Early studies that examined the effects of nonspecific inhibition of nitric oxide on ischemic brain damage found contradictory results, that is, enhanced, reduced, or no change in cerebral ischemic damage. Since these early studies, the use of more specific inhibitors of NOS has yielded more consistent results. Selective inhibition of nNOS has been shown to reduce cerebral ischemic damage, including cerebral edema. Similarly, the use of specific inhibitors of iNOS has been shown to reduce postischemic infarct size following cerebral ischemia. Further, the use of NOS-deficient mice has strengthened the position that eNOS activity might be protective (due to the effects of eNOS on cerebrovascular hemodynamics), while nNOS and iNOS activity may be detrimental to the ischemic brain. Thus, an understanding of the precise roles for the various isoforms of NOS in ischemia-induced damage to the brain, including an increase in permeability of the blood-brain barrier, may lead to new therapeutic approaches for the treatment of many cere-brovascular disorders, including stroke.

Bacterial Infection

Bacterial meningitis remains a life-threatening illness with high morbidity and mortality rate in infants, children, and adults. A characteristic feature of bacterial meningitis, which appears to contribute to the adverse neurological outcome, is an inflammatory response to endotoxins that produces disruption of the blood-brain barrier. Investigators have examined the pathology of meningitis by examining the effects of lipopolysaccharide on the permeability of the blood-brain barrier. Lipopolysaccharide is a major constituent of the outer membrane of Gram-negative bacteria and plays a pivotal role in initiating inflammation of the brain. Treatment of the cerebral circulation with lipopolysaccharide produces an increase in the permeability of the blood-brain barrier. Further, treatment of the cerebral microcirculation with aminoguanidine, to inhibit iNOS, inhibited lipopolysaccharide-induced increases in permeability of the blood-brain barrier. Thus, it appears that the synthesis/release of nitric oxide plays a critical role in changes in permeability of the blood-brain barrier during bacterial infections.

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