Publisher Summary This chapter discusses the role of free radicals and catalytic metal ions in human disease. The importance of transition metal ions in mediating oxidant damage naturally leads to the question as to what forms of such ions might be available to catalyze radical reactions in vivo . The chapter discusses the metabolism of transition metals, such as iron and copper. It also discusses the chelation therapy that is an approach to site-specific antioxidant protection. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. A wide range of techniques is available to measure the rate of this process, but none is applicable to all circumstances. The two most popular are the measurement of diene conjugation and the thiobarbituric acid (TBA) test, but they are both subject to pitfalls, especially when applied to human samples. The chapter also discusses the essential principles of the peroxidation process. When discussing lipid peroxidation, it is essential to use clear terminology for the sequence of events involved; an imprecise use of terms such as initiation has caused considerable confusion in the literature. In a completely peroxide-free lipid system, first chain initiation of a peroxidation sequence in a membrane or polyunsaturated fatty acid refers to the attack of any species that has sufficient reactivity to abstract a hydrogen atom from a methylene group.

Role of free radicals and catalytic metal ions in human disease: an overview.

Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.

Neurodegenerative diseases and oxidative stress.

Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression by pathogens. In the last decade, there has been much interest in the potential health benefits of dietary plant polyphenols as antioxidant. Epidemiological studies and associated meta-analyses strongly suggest that long term consumption of diets rich in plant polyphenols offer protection against development of cancers, cardiovascular diseases, diabetes, osteoporosis and neurodegenerative diseases. Here we present knowledge about the biological effects of plant polyphenols in the context of relevance to human health.

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Plant Polyphenols as Dietary Antioxidants in Human Health and Disease

Irrespective of the morphological features of end-stage cell death (that may be apoptotic, necrotic, autophagic, or mitotic), mitochondrial membrane permeabilization (MMP) is frequently the decisive event that delimits the frontier between survival and death. Thus mitochondrial membranes constitute the battleground on which opposing signals combat to seal the cell's fate. Local players that determine the propensity to MMP include the pro- and antiapoptotic members of the Bcl-2 family, proteins from the mitochondrialpermeability transition pore complex, as well as a plethora of interacting partners including mitochondrial lipids. Intermediate metabolites, redox processes, sphingolipids, ion gradients, transcription factors, as well as kinases and phosphatases link lethal and vital signals emanating from distinct subcellular compartments to mitochondria. Thus mitochondria integrate a variety of proapoptotic signals. Once MMP has been induced, it causes the release of catabolic hydrolases and activators of such enzymes (including those of caspases) from mitochondria. These catabolic enzymes as well as the cessation of the bioenergetic and redox functions of mitochondria finally lead to cell death, meaning that mitochondria coordinate the late stage of cellular demise. Pathological cell death induced by ischemia/reperfusion, intoxication with xenobiotics, neurodegenerative diseases, or viral infection also relies on MMP as a critical event. The inhibition of MMP constitutes an important strategy for the pharmaceutical prevention of unwarranted cell death. Conversely, induction of MMP in tumor cells constitutes the goal of anticancer chemotherapy.

Mitochondrial Membrane Permeabilization in Cell Death

A new automated colorimetric method for measuring total oxidant status.

Objective: To determine whether serum trace metals and oxidative species are related to abnormal cognition in AD. Methods: The authors studied serum peroxides, copper, iron, transferrin, and antioxidant capacity in 79 patients with AD (mean age 74.3 years; 25 men, 54 women) and in 76 cognitively normal individuals (mean age 70.1 years; 33 men, 43 women). The relation of these oxidative and trace metals to APOE e4 allele frequency, neuropsychological performance, and cerebrovascular or atrophic burden, as estimated by brain MRI and ultrasonography of cerebral vessels, was evaluated. Results: Copper level was higher ( p p p APOE e4 allele ( p = 0.004). Conclusions: Copper may play a role in neurodegenerative processes in AD, and serum copper measurement may prove to be a peripheral diagnostic marker for AD.

Elevation of serum copper levels in Alzheimer’s disease

Brain aging and the most diffused neurodegenerative diseases of the elderly are characterized by oxidative damage, redox metals homeostasis impairment and inflammation Food polyphenols can counteract these alterations in vitro and are therefore suggested to have potential anti-aging and brain-protective activities, as also indicated by the results of some epidemiological studies Despite the huge and increasing amount of the in vitro studies trying to unravel the mechanisms of action of dietary polyphenols, the research in this field is still incomplete, and questions about bioavailability, biotransformation, synergism with other dietary factors, mechanisms of the antioxidant activity, risks inherent to their possible pro-oxidant activities are still unanswered Most of all, the capacity of the majority of these compounds to cross the blood-brain barrier and reach brain is still unknown This commentary discusses recent data on these aspects, particularly focusing on effects of curcumin, resveratrol and catechins on Alzheimer's disease

Benefits from Dietary Polyphenols for Brain Aging and Alzheimer’s Disease

Objective: To assess whether serum copper in Alzheimer disease (AD) correlates with cognitive scores, β-amyloid, and other CSF markers of neurodegeneration. Methods: The authors studied copper, ceruloplasmin, total peroxide, and antioxidants levels (TRAP) in serum; β-amyloid in plasma; and copper, β-amyloid, h-tau, and P-tau in the CSF of 28 patients with AD and 25 healthy controls, in relation to clinical status. Results: Serum copper ( p p = 0.002), a copper fraction unexplained by ceruloplasmin ( p p = 0.001) were increased in AD, whereas serum TRAP ( p = 0.03) and CSF β-amyloid were decreased ( p r = 0.6; p = 0.05). CSF markers of AD correlated with serum copper variables. CSF copper was partially dependent on the serum copper fraction unexplained by ceruloplasmin ( t = 2.2, p = 0.04). CSF β-amyloid seemed to be related to serum copper ( r = −0.46; p = 0.002). Mini-Mental Status Examination scores correlated positively with β-amyloid ( r = 0.46, p = 0.002) and inversely with copper unexplained by ceruloplasmin ( r = −0.45, p = 0.003). Conclusions: The authors9 results confirm the existence of changes in copper component distribution, particularly the copper fraction unexplained by ceruloplasmin and support the hypothesis of a β-amyloid and copper connection in Alzheimer disease.

Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tau

Quinone toxicity in hepatocytes without oxidative stress

Objective: To assess the role of serum copper in relation to ceruloplasmin and other peripheral markers of inflammation in Alzheimer disease (AD). Methods: The authors studied serum levels of copper, ceruloplasmin, and transferrin, as well as total peroxides, antioxidants, and other peripheral markers of inflammation in 47 patients with AD, 24 patients with vascular dementia (VaD), and 44 healthy controls. Biochemical variables were related to the patients' and controls' clinical status. Results: The authors found that copper (p < 0.001), peroxides (p = 0.026), and ceruloplasmin (p = 0.052) were increased and TRAP was decreased (p = 0.006) in patients with AD, while no other markers of inflammation were altered. The calculation of the ratio between copper and ceruloplasmin suggested the presence in the serum of AD patients, but not of VaD or normal controls, of a large pool of non-ceruloplasmin-bound copper. Conclusions: Changes in the distribution of the serum copper components, consisting of an increase of a copper fraction not explained by ceruloplasmin, seem to be characteristic of Alzheimer disease and may be implicated in the pathogenesis of the disease.

Luisa Rossi

Papers

Elevation of serum copper levels in Alzheimer’s disease

Benefits from Dietary Polyphenols for Brain Aging and Alzheimer’s Disease

Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF β-amyloid, and h-tau

Quinone toxicity in hepatocytes without oxidative stress

Excess of serum copper not related to ceruloplasmin in Alzheimer disease