2Library and Information Access, San Diego State University, San Diego, CA, USA
Symptoms for Lewy Body (LB) are addressed in detail from the literature. Symptoms for AD, PD, and dementia are included in the original reports [1-3]. The probability of the following symptoms for LB is as follows. A decline in thinking abilities that interfere with everyday life is always associated with LB. Planning, problem-solving abilities difficulty with direction and spatial relationships, fluctuating cognitive ability, and severe sensitivity to medicine used to treat hallucinations are likely. It is also possible that there will be significant memory loss, language problems, changes in mood, sleep behavior disorder, hallucinations, changes in gait, slower movement, problems using hands, tremors, and balance problems.
LB fits into the unifying mechanism which has been widely applied in a previous article involving electron transfer (ET), reactive oxygen species (ROS) and oxidative stress (OS) . This unifying mechanism argues that the preponderance of bioactive substances, usually as the metabolites, incorporate ET functionalities. We believe these ET-metabolites play an important role in physiological responses. The main group includes quinones (or phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species). Resultant redox cycling is illustrated in Scheme 1. In vivo redox cycling with oxygen can occur, giving rise to OS through generation of ROS, such as hydrogen peroxide, hydroperoxides, alkyl peroxides, and diverse radicals (hydroxyl, alkoxyl, hydroperoxyl, and superoxide) (Scheme 1). Cellular and mitochondrial enzymes can also perform catalytically in the reduction of O2.
ROS can be beneficial, but at high levels toxic effects often predominate. There are various sources for these species . NAPDH oxidase is an important producer of the ROS in various organs. The G72 gene increased radical generation in cells. The gene acts as an activator of oxidase. ROS generated by NO synthase have been implicated in an array of harmful behaviors. Mitochondia provide another source of ROS-OS which appears to contribute to aging. Leakage of electrons occurs in the ET chain which react with oxygen to produce superoxide, a precursor of other ROS. Other examples of ROS producers are cytochrome P450, metal complexes, monoamine oxidase and microglia.
A variety of pathological processes may underlie various brain diseases, including OS, such as apoptosis, inflammation, and nerve problems . Patients with LB disorders show cognitive decline resulting from a variety of pathologies. The severity of PD dementia correlates significantly with the density of LB in the brain . Associated OS may play a role in the pathogenesis. Various studies demonstrated enhanced markers of OS in the brain of LB patients . Studies of LB disorders revealed OS damage to a serious extent . Various pathogenic processes are associated with LB diseases . Other factors are inflammation and apoptosis.
Immunohistochemical visualization of ubiquitin-positive and α-synuclein (α-syn) in LB has played an important part in revealing the prevalence of this condition . α-Syn, a key pathology of the brain, is a major protein component of LB . The review deals with α-syn aggregation and the mechanism involved in the role played by mitochondrial dysfunction. α-Syn is the major protein in LB . α-Syn is upregulated in response to toxicity. Acute OS leads to the accumulation of α-syn. There is further support for a “two hit” hypothesis for LB involving protective upregulation of α-syn from mild stress and degeneration of neurons. Data suggest the possibility that OS upregulates α-syn . This finding supports OS as a factor in LB disorders. OS, inflammation and α-syn overexpression are risk factors in LB disorders . OS enables α-syn aggregation leading to a pathological cycle.
Transition metals, such as Cu, are involved in LB . The relationship between α-syn and metal catalyzed oxidation represent a concern in treatment of these diseases. Cu-dependent enzymes are important contributors to defense by AOs. Free Cu is related to LB formation . Decreased bound Cu may enhance Fe levels and associated OS. Regarding therapy, Cu supplementation may represent a therapy, while Cu chelation may aggravate the pathology. However, excess intake of Cu is not a significant factor in these disease studies . AGE are markers of OS induced by transition metals, inducers of protein crosslinking, and free radical formation by various processes . Evidence indicated that AGE promotion of LB reflects early causative changes. Therefore, transition metals can function as both AOs and generators of ROS-OS.
One of the most important classes of AOs for brain illnesses are comprised of phenols and phenolic ethers. Melatonin (figure 1), a phenolic ether, from the pineal gland, exhibits beneficial effects as an AO and in neuroprotection . Polyphenols, such as curcumin (figure 2) and masoprocol (figure 3), phenol and phenolic ether, can function as prophylactics for ROS induced damage, protein misfolding, and neurodegenerative diseases, e.g. LB . Phenolic ethers can undergo cleavage to AO phenols .
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