Oxidative Stress in Alzheimer’s Disease: Are We Connecting the Dots?

Abstract

Redox impairment is a prominent feature of Alzheimer's disease (AD). It has led to the "oxidative stress hypothesis", which proposes antioxidants as beneficial therapeutic tools in AD treatment. To date, a wide variety of antioxidants have been examined as neuroprotectants. However, success has been elusive in clinical trials. Several factors have contributed to this failure, including the complexity of the redox system in vivo. Potentially critical aspects include the fine-tuned equilibrium between antioxidant defenses and free radical production, the lack of specific antioxidant target(s), and the inherent difficulty in delivering antioxidants where they are needed. Herein, we highlight significant progress in the field. Future directions of antioxidant research are also presented.

Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

“…Among these pathological conditions, Alzheimer's disease (AD) and other dementias are increasing in the ageing populations and their economical and social impact is becoming a worrisome burden 4 . Besides aggregation of misfolded proteins and general neuronal depletion, oxidative stress is being investigated as one of the factors contributing to AD development, although antioxidant therapies have proved unsuccessful so far 5 . In this context, the comprehension of the molecular basis of AD is crucial to define the underlying neurodegenerative mechanisms and to develop new drugs.…”

“…MAOs are mitochondrial membrane proteins that regulate the levels of monoamine neurotransmitters in both CNS and peripheral tissues by oxidizing the substrate amino group through the enzyme-bound FAD cofactor, which is then reoxidized by molecular oxygen with the release of hydrogen peroxide 8 . 5 (Please insert Figure 1 here)…”

Shogaol–huprine hybrids: Dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties

“…6,7 Disappointingly, like in the case of Aβ-directed drug candidates the clinical testing of antioxidants has met with very limited success. 6,7 Even though a low bioavailability of antioxidants has been suggested as a possible reason of failure in clinical trials, their lack of clinical efficacy has been also ascribed to the fact that oxidative stress may not be the sole cause of AD, 8,9 as it would be also the case of Aβ and tau pathologies. 10 Conversely, all these processes likely display a similarly important role in a complex pathological network, making their simultaneous modulation necessary, i.e.…”

“…a multitarget therapeutic intervention, in the pursuit of effective anti-Alzheimer treatments. 8,9 Figure 1. Structures of the natural antioxidant [6]-shogaol and the AChE inhibitor huprine Y.…”

“…8 Usually, the starting point for the design of such compounds is the structure of a known AChE inhibitor, which is linked to an antioxidant pharmacophoric moiety, [11][12][13][14][15][16][17][18] e.g. phenolics and polyphenolics derived fragments.…”