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
• manganese
• heavy metals

Article highlights

• Manganese (Mn) is an essential trace element that is required for several physiological process and it has an important function as cofactor of numerous enzymes required for glial and neuronal cells. However, the Mn overload may result in neurotoxicity and development of diseases.

• Neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), prion diseases are global public health concern. These diseases are characterized by progressive dysfunction and loss of neurons in certain anatomical regions with a variety of clinical presentations. Environmental factors such as Mn exposure may be involved in the etiology and progression of these diseases.

• Chelation therapy using CaNa₂EDTA and PAS have been utilized to treatment of symptoms related to Mn over exposure. However, several limitations, such as low bioavailability and efficacy, absence of specificity of chelating molecules, difficulty to cross the blood-brain barrier, and potential common and severe adverse effects in patients receiving chelation therapy hinder effective treatment.

• Several natural compounds and isolated phytochemicals have been studied in the treatment of Mn neurotoxicity. Phenolic compounds, such as rosmarinic acid, cyaniding, and delphinidin, and silymarin, an antioxidant flavonoid, have demonstrated promising results in mitigating Mn neurotoxicity.

• Bioinformatic analysis to identify key genes and pathways, predicting possible molecular mechanisms underlying Mn-induced neurotoxicity and neurodegeneration and new approaches such as proteomic and metabolomic analyses are essential to better understand the molecular mechanisms underlying Mn-induced neurodegenerative disorders, as well as the identification of new targets for its treatment.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the National Institute of Environmental Health Sciences to MA [NIEHS R01ES007331 and R01ES10563] and EL [R01 ES024756].