Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterised by impairments in the cognitive domains associated with orientation, recording, and memory. This pathology results from an abnormal deposition of the β-amyloid (Aβ) peptide and the intracellular accumulation of neurofibrillary tangles. Mitochondrial dysfunctions play an important role in the pathogenesis of AD, due to disturbances in the bioenergetic properties of cells. To date, the usual therapeutic drugs are limited because of the diversity of cellular routes in AD and the toxic potential of these agents. In this context, alpha-lipoic acid (α-LA) is a well-known fatty acid used as a supplement in several health conditions and diseases, such as periphery neuropathies and neurodegenerative disorders. It is produced in several cell types, eukaryotes, and prokaryotes, showing antioxidant and anti-inflammatory properties. α-LA acts as an enzymatic cofactor able to regulate metabolism, energy production, and mitochondrial biogenesis. In addition, the antioxidant capacity of α-LA is associated with two thiol groups that can be oxidised or reduced, prevent excess free radical formation, and act on improvement of mitochondrial performance. Moreover, α-LA has mechanisms of epigenetic regulation in genes related to the expression of various inflammatory mediators, such PGE2, COX-2, iNOS, TNF-α, IL-1β, and IL-6. Regarding the pharmacokinetic profile, α-LA has rapid uptake and low bioavailability and the metabolism is primarily hepatic. However, α-LA has low risk in prolonged use, although its therapeutic potential, interactions with other substances, and adverse reactions have not been well established in clinical trials with populations at higher risk for diseases of aging. Thus, this review aimed to describe the pharmacokinetic profile, bioavailability, therapeutic efficacy, safety, and effects of combined use with centrally acting drugs, as well as report in vitro and in vivo studies that demonstrate the mitochondrial mechanisms of α-LA involved in AD protection.
Highlights
Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disorder, impairing brain functions such as memory, thinking, and personality [1, 2]
Mitochondrial damage in the neurons of individuals with AD has been known for 25 years [39], and currently, more and more evidence points to mitochondria as a strong therapeutic target in several diseases associated with aging, including AD [43]
Oxidative damage caused by increased reactive oxygen species (ROS) in neurons is a consequence of a number of mechanisms associated with senescence, and the role of mitochondria seems to be crucial in the cascade of AD pathology events
Summary
Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disorder, impairing brain functions such as memory, thinking, and personality [1, 2]. The main source of ROS is mitochondria, and the dysfunction of this organelle in neurons may be one of the initiating processes of neurodegeneration [13] Mitochondrial damage, such as mitochondrial disruption, can cause astrocytes to increase matrix production due to calcium or ROS release, activating caspases and generating cell death [21]. Recent reviews report that other natural products, such as flavonoids, polyphenols, alkaloids, and glycosides, exhibit neuroprotective mechanisms, due to changes in the expression of transcription factors, in signalling pathways, as well as the activation of autophagy mechanisms, among others [17, 22,23,24] In this context, alpha-lipoic acid (α-LA) is a naturally occurring molecule, with antioxidant and anti-inflammatory properties [25, 26], which plays several roles in the pathogenesis of neurodegenerative diseases, such as AD, and acts as a neuroprotective agent [27]. This review provides an overview of molecular mechanisms in mitochondrial function in the AD context, as well as pharmacokinetic and therapeutic safety parameters of α-LA
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