Manganese-induced neurodegenerative diseases and possible therapeutic approaches

Abstract

Introduction: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion disease represent important public health concerns. Exposure to high levels of heavy metals such as manganese (Mn) may contribute to their development.

Areas covered: In this critical review, we address the role of Mn in the etiology of neurodegenerative diseases and discuss emerging treatments of Mn overload, such as chelation therapy. In addition, we discuss natural and synthetic compounds under development as prospective therapeutics. Moreover, bioinformatic approaches to identify new potential targets and therapeutic substances to reverse the neurodegenerative diseases are discussed.

Expert opinion: Here, the authors highlight the importance of better understanding the molecular mechanisms of toxicity associated with neurodegenerative diseases, and the role of Mn in these diseases. Additional emphasis should be directed to the discovery of new agents to treat Mn-induced diseases, since present day chelator therapies have limited bioavailability. Furthermore, the authors encourage the scientific community to develop research using libraries of compounds to screen those compounds that show efficacy in regulating brain Mn levels. In addition, bioinformatics may provide novel insight for pathways and clinical treatments associated with Mn-induced neurodegeneration, leading to a new direction in Mn toxicological research.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; heavy metals; manganese.

Figure 1.

Potential mechanisms of chelators and phytoextracts against Mn-induced neurotoxicity. Briefly, EDTA and PSA prevent Mn²⁺ from entering the cell, thus reducing its intracellular level and toxic effects. Phytoextracts and particular phytochemicals were shown to counteract mechanisms of Mn²⁺-induced neurotoxicity including NF-κB activation with subsequent proinflammatory cytokine expression (E. amoenum); mitochondrial dysfunction resulting in ROS overaccumulation and oxidative stress (G. africanum, E. amoenum, E. supina, M. officinalis), as well as apoptotic signaling (E. amoenum); alteration of protein folding, unfolded protein response, and endoplasmic reticulum stress (E. amoenum). Natural extracts were also shown to prevent reduction of catecholamine levels due to autooxidation (E. amoenum) and counteract cholinergic dysfunction (G. africanum). Other plant extracts sharing similar phytochemical spectrum may also possess protective effect. It is also highly expected that these phytoextracts or other phytochemicals may modulate specific mechanisms of Mn²⁺-induced neurodegeneration, including amyloid-β (Alzheimer’s disease) and α-synuclein (Parkinson’s disease) aggregation, although direct evidence for these effects have yet to be established. EDTA - ethylenediaminetetraacetate, PSA – para-aminosalicylic acid, ACh - acetylcholin, AChE - acetylcholinesterase, ROS – reactive oxygen species, OxS – oxidative stress, UPR – unfolded protein response, ERS – endoplasmic reticulum stress, CytC – cytochrome c, TNFα – tumor necrosis factor α, IL-1β – interleukin 1β.