Prospects for redox-based therapy in neurodegenerative diseases.

Accumulating evidence supports a primary role for perturbations in redox metabolism in the pathogenesis of many neurodegenerative diseases. This evidence derives mainly from molecular genetic analysis, direct observation from post-mortem human brain, and biochemical, pathologic, and therapeutic studies in transgenic and other animal models of neurodegeneration. We review here the evidence for redox-mediated pathogenesis in neurodegenerative diseases. The emerging class of redox-based therapeutic agents is then discussed. Drugs of this class are distinguished by their proximate effect, which is oxidative and not phosphorylative.

Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation.

Responses to increased oxidative stress may be the common mechanism responsible for the varied cytopathology of Alzheimer disease (AD). A possible link in support of this hypothesis is that one of the most striking features of AD, the abnormal accumulation of highly phosphorylated tau and neurofilament proteins, may be brought about by extracellular receptor kinase (ERK) whose activation is a common response to oxidative stress. In this study, we demonstrate that activated ERK is specifically increased in the same vulnerable neurons in AD that are the site of oxidative damage and abnormal phosphorylation. These findings suggest that ERK dysregulation, likley resulting from oxidative stress, could play an important role in the increased phosphorylation of cytoskeletal proteins observed in AD.

Involvement of free oxygen radicals in beta-amyloidosis: an hypothesis.

Compelling evidence suggests that cerebral deposition of aggregating beta-amyloid protein may trigger the neurodegenerative cascades of Alzheimer's disease, Down syndrome, and, to a lesser degree, normal aging. We propose further that free oxygen radicals are critically involved in beta-amyloidosis. Apart from the established role of free radicals in other amyloidoses, our proposal is consistent with a large number of findings. Among these are (a) the salient relationship of Alzheimer's disease with aging and the increase in free oxygen radical liberation with advancing age; (b) biochemical and analytic epidemiologic evidence that free radical formation is increased in the disorder; (c) preliminary evidence that quenching free radicals slows the clinical progression of Alzheimer's disease; (d) the early and invariable beta-amyloid accumulation in trisomy 21, a syndrome associated with elevated free radical activity and with concomitant high levels of beta-amyloid precursor protein; (e) other factors that may be associated with increased liberation of free oxygen radicals and deposition of beta-amyloid protein. Possible mechanisms by which free radicals might modulate beta-amyloidosis are discussed.

Regional differences in pulmonary vascular resistance in the same patient. A study of partial anomalous pulmonary venous return, intact atrial septum, and mitral stenosis before and after surgical correction.

Using hemodynamic and radionuclide perfusion data, we measured regional pulmonary vascular resistances in a patient with mitral stenosis and anomalous pulmonary venous drainage with intact atrial septum before and after surgical correction. Pulmonary vascular resistance in the right upper lung region that had anomalous drainage to a normal-pressure right atrium was compared to resistance of a region in the left upper lung similar in size that had normal drainage to a high-pressure left atrium. Preoperatively, pulmonary vascular resistance in both regions was elevated but was considerably higher in the left upper lung region. Postoperatively, pulmonary vascular resistance fell substantially in the left upper lung with the fall in left atrial pressure, whereas it changed minimally in the right upper lung after elimination of the left-to right shunt. These findings are related to vascular abnormalities on biopsies obtained from both regions.

Valve replacement for aortic regurgitation: long-term follow-up with factors influencing the results.

One hundred consecutive cases of valve replacement for aortic regurgitation performed between 1967--1971 were analyzed to identify and quantitate factors related to a favorable result. Of 83 perioperative survivors, 78% (n = 65) became asymptomatic and 58% (n = 48) were alive 5--9 years postoperatively. The cause of aortic regurgitation affected both the speed of progression of symptoms and the postoperative result. Death due to myocardial failure may be prevented by optimal timing of operation. Accordingly, we identified variables that discriminated between patients who had an excellent postoperative result and those who died of myocardial failure. The most important discriminators were the severity (p = 0.03) and duration (p = 0.04) of dyspnea, the extent of therapy for heart failure (p = 0.001), physical findings of left ventricular failure (p = 0.002), the cardiothoracic ratio (p = 0.007), the resting pulmonary capillary wedge pressure (p = 0.01), and a cardiac index less than 2.2 1/min/m2 (p = 0.03). The data suggest that evidence of left ventricular failure, even of mild degree, is an indication for operation in patients with severe aortic regurgitation.

Influence of etiology of atrial fibrillation on incidence of systemic embolism.

Atrial fibrillation is well known to increase greatly the risk of systemic arterial embolism in patients with mitral valve disease. In light of the clinical frequency of embolism in patients with atrial fibrillation due to other types of heart disease, a study was made of embolic occurrences in 333 autopsy patients with atrial fibrillation associated with various kinds of heart disease. Considering only symptomatic emboli with pathologic or surgical confirmation, embolism occurred in 41% of patients with mitral valve disease, 35% of those with ischemic heart disease, 35% of those with coexisting mitral and ischemic heart disease and 17% of those with "other" types of heart disease. Embolism was found in only 7% of a control group of 58 autopsy patients with ischemic heart disease without atrial fibrillation. These findings suggest a high risk of embolism from atrial fibrillation of any origin, but particularly from that caused by ischemic heart disease and mitral valve disease.

Survival following free rupture of left ventricular aneurysm: report of a case.

A 50-year-old man sustained free rupture of the left ventricle four weeks following a massive anterior myocardial infarction. The rupture occurred at the junction between a bulging left ventricular aneurysm that was not yet fibrotic and normal myocardium without evidence of fresh myocardial infarction. Accurate preoperative diagnosis aided by echocardiography and right heart catheterization made possible a planned surgical approach. Postoperative support with intraaortic balloon pumping appeared to be beneficial in maintaining statisfactory cardiac function until an adequate stroke volume could be reestablished, presumably by an increase in left ventricular volume.

Pulmonary atresia with ventricular septal defect: report of the oldest known surviving case.

The case of a 54-year-old housewife, oldest published survivor with pulmonary atresia and a ventricular septal defect (pseudotruncus arteriosus), is reported. Her remarkably favorable course is likely related to the absence of progressive hemodynamic changes, with moderate pulmonary flow adequate for nearly normal arterial oxygenation yet without increasing pulmonary vascular resistance. This case reemphasizes the relationship of longevity to pulmonary blood flow volume with this defect.