Exploring the Neuroprotective Role of Selenium: Implications and Perspectives for Central Nervous System Disorders

Abstract

Selenium (Se) is a crucial element in selenoproteins, key biomolecules for physiological function in vivo. As a selenium-rich organ, the central nervous system can express all 25 kinds of selenoproteins, which protect neurons by reducing oxidative stress and inflammatory response. However, decreased Se levels are prevalent in a variety of neurological disorders, which is not conducive to the treatment and prognosis of patients. Thus, the biological study of Se has emerged as a focal point in investigating the pivotal role of trace elements in neuroprotection. This paper presents a comprehensive review of the pathogenic mechanism of neurological diseases, the protective mechanism of Se, and the neurological protective function of selenoproteins. Additionally, the application of Se as a neuroprotective agent in neurological disorder therapy, including ischemic stroke, Alzheimer's, Parkinson's, and other neurological diseases, is summarized. The present review aims to offer novel insights and methodologies for the prevention and treatment of neurological disorders with trace Se, providing a scientific basis for the development of innovative Se-based neuroprotectants to promote their clinical application against neurological diseases.

Keywords: nervous system disorders; neuroprotection; selenium; selenoproteins.

FIGURE 1

Application and mechanism of Se in neurological diseases.

FIGURE 2

The neuroprotective activity mechanism of Se by inhibiting ferroptosis in stroke. (A,B) GPX4 prevents oxidative stress‐induced ferroptosis [78]. Copyright 2018, Cell Press. (C) Pathological cascade induced by ferroptosis [79].

FIGURE 3

The application of selenoprotein activity and treatment by Se in stroke. (A) Pharmacological Se supplementation effectively inhibits ferroptosis in hemorrhagic stroke; (B) Intraperitoneal injection of Tat SelPep can improve sensory (i) and spatial (ii) neglect and reduce the size of cerebral infarction (iii) in mice [85]. Copyright 2019, Cell Press. (C) HDAC9 knockdown alleviates neuronal ferroptosis by enhancing GPX4 [90]. (D) GPX overexpression improves neuronal survival after stroke by clearing ROS and inhibiting cytochrome C release [91]. Copyright 2003, American Heart Association.

FIGURE 4

The main pathological mechanism of AD: (A,B) Deposition of Aβ protein and Tau protein aggregation [97]. Copyright 2019, Cell Press. (C) Brain‐gut axis autophagy dysfunction [101, 102]. Copyright 2020, Wiley‐VCH.

FIGURE 5

Application of Se in the treatment of AD. (A) Selenate treatment prevented axonal degeneration of different neuronal populations in K3 mice [107]. Copyright 2010, National Academy of Sciences. (B) Autophagy, antioxidant, and anti‐inflammatory signaling pathways regulated by Se‐enriched bioactive ingredients targeted AD [114]. (C) The overexpression of SelK in microglia of AD mice suggests that SelK is involved in the regulation of immune function in the central nervous system [117]. Copyright 2019, Mary Ann Liebert. (D) Multi‐functional double Se nanospheres (CLNDSe) can regulate the expression of GPX4 to treat AD by disrupting the aggregation of Aβ42 and inhibiting hyperphosphorylation of Tau protein [118]. Copyright 2023, Elsevier.

FIGURE 6

Multifaceted pathological mechanisms of PD. (1) Mechanism of mitochondrial dysfunction, including α‐synuclein, gene mutations, and oxidative stress suppress complex I [142]. (2) Abnormal dopamine metabolism‐induced oxidative stress and neuromelanin accumulation [143, 144]. (3) Microglia was activated by neuromelanin, α‐synuclein, and dead neurons [145]. The interplay of these mechanisms led to the degeneration of dopaminergic neurons, collectively driving the onset and progression of PD.

FIGURE 7

Therapeutic application of Se in Parkinson's disease. (A) Pathogenesis of PD through dopaminergic neuron degeneration, which is exacerbated by the loss of antioxidant enzyme GPX4 activity [159]. (B) Human serum albumin/Se nanoparticles provided neuroprotection to dopaminergic neurons via modulated Keap1‐Nrf2‐SOD signaling pathways [160]. Copyright 2023, American Chemical Society. (C) Administration of low‐dose Se–Na significantly improved motor performance [161]. (D) Se supplementation alleviated neuroinflammation by enhancing SelP and GPX4 expression in the hippocampus of mice [32]. Copyright 2023, Elsevier.

FIGURE 8

Application of Se in the treatment of Huntington's disease. (A) Sodium selenite alleviated oxidative stress, neurodegeneration and mutant Huntington protein aggregation in HD mice by regulating selenoproteins [172]. Copyright 2014, Elsevier. (B) GSH‐related antioxidants are increased in the striatum and cortex of FL‐mHtt mice [173]. Copyright 2012, Elsevier. (C) GPX6 as a suppressor of mutant Huntingtin toxicity [174]. Copyright 2014, National Academy of Sciences. (D) Nano‐Se alleviated oxidative stress and neurological dysfunction in transgenic HD models of Caenorhabditis elegans [168]. Copyright 2019, American Chemical Society.

FIGURE 9

Application of Se in the treatment of other central neuronal diseases. (A) Mechanisms of Se in the treatment of ASD and Epileptic seizure by anti‐inflammatory, anti‐oxidative stress and regulates neurotransmitter [15, 179, 180]. (B) Selenium‐containing ROS‐responsive ointment suppresses oxidative stress and inflammation to provide synergistic treatment of TBI [185]. Copyright 2024, Elsevier. (C) Se@BDP‐DOH using hydrophobic–hydrophobic interactions to accurately map the redox status and eliminate oxidative stress in SCI [187]. Copyright 2023 Wiley‐VCH. (D) TSIIA@SeNPs‐APS can increase GPX activity and decrease MDA content, possibly through its metabolism to L‐Selenocystine (SeCys₂) and by regulating antioxidant selenoproteins to protect spinal cord neurons from oxidative stress‐induced damage [188]. Copyright 2020, BioMed Central.