Multiple Antioxidants in the Prevention and Treatment of Alzheimer Disease: Analysis of Biologic Rationale

Abstract

The etiology of Alzheimer disease (AD) is not well understood; therefore, neither prevention strategies nor long-term effective treatment modalities are available for this disease. Based on laboratory and clinical studies, it appears that reactive oxygen species (ROS) and reactive nitrogen species (RNS) that are generated extracellularly and intracellularly by various mechanisms are among the major intermediary risk factors that initiate and promote neurodegeneration in idiopathic AD. Therefore, multiple antioxidant supplements could be useful in the prevention of AD, and as an adjunct to standard therapy in the treatment of AD. The products of inflammatory reactions such as prostaglandins (PGs; PGE1 and PGA1), free radicals, cytokines, and complement proteins are neurotoxic. Nonsteroidal antiinflammatory drugs (NSAIDs), which inhibit the synthesis of PGs, reduce the rate of deterioration of cognitive functions in patients with advanced AD. Cholinergic drugs are routinely used in the treatment of AD to improve cognitive functions. Therefore, we propose that a combination of multiple antioxidants and NSAIDs may be more beneficial in the prevention of AD, and that this combination taken together with cholinergic drugs may be more effective in the treatment of AD than the individual agents alone. We also hypothesize that, in idiopathic AD, epigenetic components of neurons such as mitochondria, membranes, other membranous structures, and protein modifications--rather than the genes of neurons--are the primary targets for the action of neurotoxins including free radicals. In some familial AD, mutations in amyloid precursor protein and presenilins are associated with the risk of early onset of this disease; however, their mechanisms of action are not fully understood.

Protection of Human Endothelial Cells From Oxidative Stress

“…[1][2][3][4][5] Recent insights into the p21 Ras ERK1/2 signaling cascade suggest that Ras is directly involved in the regulation of the intracellular redox state. 8,18,19 HUVECs, exposed to 2 mmol/L H 2 O 2 for 2 hours, undergo apoptosis 6 to 24 hours later.…”

“…[1][2][3][4][5] A growing body of evidence suggests that the small GTPase p21 Ras is an essential mediator of the signal transduction pathway leading to cell apoptosis after oxidative injury. 6 -8 Oxidative stress and p21 Ras activate a group of kinases, the mitogen-activated protein kinase (MAPK) family, 9 including the extracellular signal-regulated kinases (ERK1/2), c-Jun NH 2 -terminal kinase (JNK or SAPK), and p38 MAPK.…”

The potential therapeutic role of Fenugreek saponin against Alzheimers disease: Evaluation of apoptotic and acetylcholinesterase inhibitory activities

“…Alzheimer's society recorded that 13% of the American population beyond age of 65 years and 50% of the Americans higher than 85 years in age have been currently estimated as AD's patients (Kim et al, 2009). Therefore, increasing the number of AD patients which reaching several million in the near future (Kim et al, 2009;Heo et al, 2004;Prasad et al, 2000;Terry and Masliah, 1991) needs a lot of money for the health care scheme of the AD (Kim et al, 2009). …”

Protective Activity of Aromatic Amines and Imines against Oxidative Nerve Cell Death

“…Nevertheless, results from standardized animal models, epidemiological studies, and from a wide array of biochemical considerations seem to indicate that certain investigational antioxidant compounds might have a profound preventive or therapeutic value (Sies, 1993;Baker et al, 1998;Parkes et al, 1998;Reiter, 1998;Leppala et al, 1999;Nourhashemi et al, 2000;Jung et al, 2001; and the above reviews). Consequently, the search for antioxidant pharmaceuticals which (i) inhibit pathogenetically relevant oxidative phenomena, (ii) readily pass the blood-brain barrier, and (iii) show a higher efficacy per dose, thereby concomitantly exhibiting a reduced risk of adverse side effects, is in the center of interest of clinically involved physicians as well as biochemically focused scientists (Harman, 1996;Behl, 1999;Prasad et al, 1999;Alexi et al, 2000;Grunblatt et al, 2000;Prasad et al, 2000;Sramek and Cutler, 2000;Wolozin and Behl, 2000;Gilgun-Sherki et al, 2001).…”