Mitochondria- and Oxidative Stress-Targeting Substances in Cognitive Decline-Related Disorders: From Molecular Mechanisms to Clinical Evidence

Abstract

Alzheimer’s disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied neurodegenerative disorder yet incurable to date. While its main postmortem brain hallmarks are the presence of amyloid-βplaques and hyperphosphorylated tau tangles, the onset of the disease seems to be largely correlated to mitochondrial dysfunction, an early event in the disease pathogenesis. AD is characterized by flawed energy metabolism in the brain and excessive oxidative stress, processes that involve less adenosine triphosphate (ATP) and more reactive oxygen species (ROS) production respectively. Mitochondria are at the center of both these processes as they are responsible for energy and ROS generation through mainly oxidative phosphorylation. StandardizedGinkgo bilobaextract (GBE), resveratrol, and phytoestrogens as well as the neurosteroid allopregnanolone have shown not only some mitochondria-modulating properties but also significant antioxidant potential inin vitroandin vivostudies. According to our review of the literature, GBE, resveratrol, allopregnanolone, and phytoestrogens showed promising effects on mitochondria in a descending evidence order and, notably, this order pattern is in line with the existing clinical evidence level for each entity. In this review, the effects of these four entities are discussed with special focus on their mitochondria-modulating effects and their mitochondria-improving and antioxidant properties across the spectrum of cognitive decline-related disorders. Evidence from preclinical and clinical studies on their mechanisms of action are summarized and highlighted.

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…61,70,71,74,[77][78][79][80] Manifestations of OS are hallmark symptoms in neurological disease, including cognitive deficits. 52,54,65,76,79,[81][82][83][84][85][86][87][88] In concert with the above, a correlation was found between OS in the CNS and demyelination, which results in the loss of integrity and proper maintenance of oligodendrocytes and their myelin sheaths, the latter being crucial for cognitive performance and higher brain function. 57,[89][90][91] Thus, inclusion of strategies for enhancing mitochondrial biogenesis, function, and protection 68,80,[92][93][94][95][96] that may also rely on pathways epigenetically induced by diet [97][98][99][100][101][102][103][104][105][106][107][108] and/or exercise 99,100,…”

IMPACT OF PHENOLIC ACIDS ON THE ENERGY METABOLISM AND LONGEVITY INC. ELEGANS

“…This results in a vicious cycle of increased ROS through age-associated mitochondrial dysfunction, which again accelerates the aging process [36]. Polyphenols, due to their potential in ROS-scavenging, have emerged as a potentially powerful strategy to ameliorate oxidative stress and thus induce health and longevity [37][38][39].…”

Steps Towards Developing Effective Treatments for Neuropsychiatric Disturbances in Alzheimer’s Disease: Insights From Preclinical Models, Clinical Data, and Future Directions

“…Mitochondrial damage has been reported in both AD (Swerdlow, 2018) and depression (Bansal and Kuhad, 2016) and both patient groups show reduced glucose metabolism using fluorodeoxyglucose (FDG) PET (Hunt et al, 2007;Wei et al, 2016;Rice and Bisdas, 2017;Fu et al, 2018). Supporting this, a Ginkgo biloba extract (GBE) that has free radical scavenging properties, enhances mitochondrial membrane potential, and increase ATP production (Lejri et al, 2019) revealed a significant effect on apathy and other NPDs in AD patients (Scripnikov et al, 2007). On the contrary, a recent RCT found no effect on NPDs when patients were treated with resveratrol which acts on several proteins important for mitochondrial function (Zhu et al, 2018).…”