Table 2 Molecules or pathways of metal chelators in treating neurodegenerative diseases
From: Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases
Compounds | Ions | Disease | Model | Molecules/pathways | Ref |
|---|---|---|---|---|---|
DFO | Iron | PD | MPTP, α-synuclein rAAV, 6-OHDA, and rotenone-induced mice | Chelate iron; Increased the expression level of GPX4 and FTH1; Induce autophagy; Activate insulin signaling and glucose metabolism | |
Iron | AD | P301L tau transgenic mice; APP/PS1 mice | Suppress ferroptosis; Inhibitor GSK-3β; Targeted HIF-1α to activate GLUT1 | ||
Iron | HD | R6/2 HD mice | Improve the motor phenotype | ||
CQ | Iron Zinc Copper | PD | Zn-treated mice injected with α-synuclein; MPTP -treated monkey model | Target iron content and ROS levels; Activate AKT/mTOR pathway; Reduce lysosomal alterations | |
Iron Zinc Copper | AD | An APP transgenic mouse tau-knockout mice | Non-specificly chelate copper-zinc; Improve cognitive behavior and decrease Aβ deposits; Resumpt Cu2+-suppressed fibril growth of Aβ (1-40) | ||
Iron Zinc Copper | HD | PC12 cells expressing Htt exon-1 R6/2 mice | Decrease mutant protein expressing polyglutamine-expanded huntingtin exon 1; Improve behavioral and pathologic phenotypes | ||
PBT434 | Iron Copper | PD | 6-OHDA and MPTP treated or hA53T α-synuclein mice; Iron-induced M17 neuroblastoma cells | Inhibit iron-mediated redox activity; Inhibit re-uptake of iron by endothelial cells; Inhibit hyposmia and accumulation of iron and copper | |
DFP | Iron | PD/AD | H2O2/iron/Aβ1–40-induced primary cortical neuron; MPP+-induced SHSY-5Y cells | Iron chelator; Protects against neuronal cell death | |
Iron | AD | Rabbits fed a cholesterol-enriched diet | Reduce Aβ and Tau phosphorylation levels; Reduce plasma iron and cholesterol levels | ||
Iron | HD | R6/2 HD mice | Remove mitochondrial iron to decrease lipid peroxidation; Improve motor endurance | ||
DFP-chromonehybrids | Iron | AD | scopolamine-induced ICR mice | MAO-B inhibitors and iron chelators for the treatment of AD | |
DL-3-n-butylphthalide | Iron | PD | Rotenone-induced rats | Improve iron deposition within SN; Inhibit serum iron levels; Inhibit ferroptosis | |
Paeoniflorin | Iron | PD | MPP+-induced primary dopaminergic neurons | Activate the Akt/Nrf2/Gpx4 pathway; Inhibit ferroptosis | |
Quercetin | Iron Copper Manganese | PD | Erastin/RSL3 and MPP+-induced cells; MPTP-induced mice, Cu-induced SH-SY5Y cells; Mn-induced SK-N-MC cells and SD rats | Inhibit ferroptosis; Modulate autophagy; Activate iNOS/NF-κB and HO-1/Nrf2 Pathways | |
Quercetin | Copper | AD | Cu-induced SH-SY5Y cells | Regulate PI3K/Akt and ERK1/2 signaling | |
Sterubin fisetin | Iron | PD | Glutamate/iodoacetic acid treated HT22 cells; LPS-treated BV-2 cells | Induce Nrf2, neurotrophic factors, inflammation restriction, and iron chelating | |
AD | RSL3 induced-HT22 cells | Restore mitochondrial homeostasis | |||
Epigallocatechin-3-gallate | Iron Copper Zinc | PD | Fe3+-induced AS-PC12 cells; MPTP-induced mice; PINK1 mutant Drosophila; | Inhibit ferroptosis; Bind to metal [Cu2+ and Zn2+]-Aβ monomers and dimers | |
Emodin | Zinc | PD | Zn-induced SH-SY5Y cells | Inhibit cell apoptosis; Reduce ROS and ER-stress levels | |
Thonningianin A | Iron | PD | 6-OHDA in zebrafish and dopaminergic neurons | Inhibit ferroptosis; Inhibit Keap1-Nrf2 protein-protein interaction; Activate Atg7-dependent autophagy | |
(-)-Clausenamide Clau | Iron | PD | MPP+-induced SH-SY5Y cells; N2a and PC12 cells; MPTP-induced mice | Scavenge lipid peroxide products; Target Ser663 on ALOX5; Inhibit ferroptosis | |
E. amoenum extract | Manganese | PD | Mn2+-treated rat | Increased catecholamine content and improved depression-like behavior | |
Euterpe oleracea Mart.extract | Manganese | PD | Mn-induced rat primary astrocytes | Inhibit oxidative stress | |
Euphorbia supina extract | Manganese | PD | Mn-induced SKNMC cells and SD rats | Regulate ER stress and it mediated apoptosis | |
Melissa officinalis aqueous extract | Manganese | PD | Mn-induced mice | Inhibit oxidative stress | |
Boldo Aqueous extract | Manganese | PD | Mn-induced D. melanogaster | Improve movement disorders | |
M30 | Iron | PD | Adult mice; MPTP-induced mice | Enhance phosphorylation of PKC, MEK, PKB/Akt, and GSK-3β | |
VAR10303 | Iron | PD | 6-OHDA-induced rat; MPTP treated mice | Selectively inhibit MAO-A and MAO-B affords iron chelating/iron-induced lipid peroxidation inhibitory | |
SK4 | Iron | PD | MPP+ and 6-OHDA induced LUHMES cells | Transport iron to the brain via LAT1; Chelate brain iron | |
GW501516 | Iron | PD | MPTP-induced mice; 6-OHDA-induced mice | PPARδ agonist; Prevent intracellular iron accumulation; Alleviate NLRP3 inflammasome-mediated neuroinflammation | |
α-Lipoic acid | Iron | PD | MPP+-induced PC12 cells | Activate PI3K/Akt/Nrf2 pathway | |
Para-aminosalicylic acid | Manganese | PD | Mn-induced Parkinsonism in humans | Reduce manganese levels | |
8a | Copper | AD | Cu2+-induced Aβ1–42 aggregation | Possess antioxidant activity; Inhibit Cu2+-induced Aβ1–42 aggregation | |
X1TMP X1Benz | Copper | AD | Cu2+-Aβ system | Diminish ROS generation | |
Curcumin | Iron Copper Zinc | AD | Aβ aggregation system | Chelate metal ions | |
CRANAD-17 | Copper | AD | APP/PS1 transgenic mice | Inhibit Aβ 42 cross-linking induced by copper | |
(-)-epigallocatechin (EGC) (-)-epicatechin-3-gallate (ECG) | Copper Zinc | AD | Cu2+/Zn2+-Aβ40 induced N2a cells | Alleviate the toxicity of Aβ oligomers and fibrils | |
Eriodictyol, | Iron | AD | APP/PS1 mice; Aβ1–42 induced HT22 cells | Activate the Nrf2/HO-1 signaling pathway; Inhibit cell apoptosis | |
Amentoflavone, | Copper | AD | 5xFAD mice | Diminish Cu2+-ascorbate redox cycling and ROS formation | |
Luteolin | Copper | AD | Copper-induced SH-SY5Y cells | Reduce Aβ secretion; Maintain mitochondrial function; Depress caspase-mediated apoptosis | |
apigenin | Copper | AD | APPsw cells | Attenuate β-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation | |
vitegnoside | Copper | AD | Copper-treated SH-SY5Y cells | Inhibit p38 MAPK/JNK pathway | |
Silibinin | Iron Copper Zinc | AD | Intracerebral streptozotocin administration in mice; Mn-induced adult rats; Copper-induced rats; Zinc-induced rats; | Improve brain energy metabolism and cholinergic function; Reduce oxidative stress and inflammation | |
Berberine | Iron | AD | 3 × Tg-AD mice | Inhibit iron levels and ferroptosis; Activate Nrf2 signaling | |
Coumarin | Copper Zinc | AD | Cu2+ and Zn2+ complexes system | Chelate metal ions; Inhibit cholinesterases or MAO-B | |
Naringin | Iron | AD | Iron-overloaded mice | Decrease nonheme iron; Reduce the formation of amyloid plaques | |
Tetrahydroxy stilbene glycoside | Iron | AD | APP/PS1 mice APP695V717I transgenic model mice | Activate GSH/GPX4/ROS and Keap1/Nrf2/ARE signaling pathway; Restore mitochondrial function; Inhibit ferroptosis; | |
1,6-O,O-diacetylbritannilactone (OABL) | Iron | AD | 5xFAD mice; oxidative stress-induced PC12 cells | Inhibit oxytosis and ferroptosis; Suppress inflammatory | |
Ginkgolide B | Iron | AD | SAMP8 mice | Mitigate oxidative stress, neuroinflammation and ferroptosis | |
Hinokitiol | Iron | AD | RSL3-induced PC12 cells 6-OHDA-induced zebrafish | As a ferroptosis inhibitor | |
Senegenin | Iron | AD | Aβ25-35 induced PC12 cells | Reverse mitochondrial Depolarization; Inhibit ferroptosis | |
alkaloid extract from African Jointfir (Gnetum africanum) | Manganese | AD | Mn-induced Drosophila melanogaster | Inhibit AChE activity and ROS levels | |
Squaramide dipeptides | Copper Iron Zinc | AD | Aβ peptide system | Selectively chelate metal ions (Cu2+, Zn2+, and Fe3+) Exhibit antioxidant properties | |
Gly-His-Lys | Copper | AD | Cu2+-Aβ complex system | Suppress ROS production | |
7-O-cinnamoyltaxifolin; 7-O-feruloyltaxifolin | Iron | AD | RSL3/Glutamate/iodoacetic acid -induced HT22 cells; LPS-treated BV-2 microglia cells; Aβ25-35-induced mice | Inhibit oxytosis, ferroptosis and ATP depletion; Reduce neuroinflammation; Modulate Nrf2/GSH signaling pathway | |
Chromone-lipoic acid conjugate | Copper | AD | H2O2-induced cell damage in PC12 cells | Inhibit butyrylcholinesterase; Possess antioxidant and copper-chelation properties | |
SNH6 | Iron Copper | AD | H2O2/copper-mediated SK-N-MC cells C. elegans | Enhance cellular NAD+/NADH ratios; Chelate iron; Inhibit copper-mediated Aβ aggregation | |
bis(7)-tacrine | Copper Iron | AD | AChE-induced amyloid-beta aggregation | Inhibit AChE; Chelate metals | |
Triethylene tetramine dihydrochloride | Copper | AD | APP/PS1 mice | Inhibit RAGE/NF-κB/BACE1 pathway | |
melatonin-trientine | Iron Copper | AD | APP/PS1 transgenic mice | Inhibit metal ion dyshomeostasis; Decrease Aβ deposition | |
Edaravone | Iron | AD | Aβ1–42-induced apoptosis of HT22 cells | Prevent TLR4/NF-κB /NLRP3 signaling pathway and ferroptosis | |
GIF-0726-r | Iron | AD | Glutamate/ erastin-induced HT22 cell | Inhibit ROS accumulation and Ca2+ influx | |
M30 | Iron | AD | APP/PS1 Tg mice | Reduce cerebral iron accumulation; Decrease AD-like phenotypes | |
H2dqpyca and H2bqch | Copper | AD | Aβ peptide/H2O2-induced SH-SY5Y cells | Interact with AChE | |
salidroside | Iron | AD | SAMP8 mice | Activate Nrf2/GPX4 axis; Inhibit neuronal ferroptosis | |
β-hydroxybutyrate | Iron | AD | MPP+-induced SN4741 cells; MPTP-induced C57BL/6 mice | Alleviate oxidative stress and ferroptosis; Target ZFP36 | |
IOE 12i | Copper Iron | AD | H2O2-induced PC12 cells | Chelate metal; Inhibit AChE; Inhibit ferroptosis, With BBB permeability | |
VU0063088 VU0026921 | Manganese | PD/AD | pdat-1: GFP worms | Modulate manganese levels independent of SMF-2 | |
MESM | Manganese | HD | MnCl2-treated murine striatal neuron lineage | Reduce excessive cellular manganese levels | |
Cu II(atsm) | Copper Zinc | ALS | SOD1G37R mice; SOD1G93A mice | Improve the metal content of mutant SOD1; Improve the lifespan and preserve motor neurons | |
ZnII(atsm) | Copper Zinc | ALS | SOD1G37R mice | Increase the levels of copper in SOD1 and overall | |
ammonium tetrathiomolybdate | Copper | ALS | SOD1G93A mice | Remove copper ions from the copper thiolate cluster of SOD1, leading to the degeneration of mutant SOD1 | |
DP-109 and DP-460 | Copper Zinc | ALS | SOD1G93A mice | Chelate calcium, copper, and zinc; Improve motor performance | |
VK28, M30 | Iron | ALS | SOD1G93A mice | Chelate iron and prevent degeneration of motor neurons | |
PBT2 | Copper Zinc | HD | R6/2 mice; C. elegans model of polyQ aggregation | Reduce toxicity; Extend lifespan; Reduce striatal atrophy; |
