Iron Chelators and Antioxidants Regenerate Neuritic Tree and Nigrostriatal Fibers of MPP+/MPTP-Lesioned Dopaminergic Neurons

Abstract

Neuronal death in Parkinson’s disease (PD) is often preceded by axodendritic tree retraction and loss of neuronal functionality. The presence of non-functional but live neurons opens therapeutic possibilities to recover functionality before clinical symptoms develop. Considering that iron accumulation and oxidative damage are conditions commonly found in PD, we tested the possible neuritogenic effects of iron chelators and antioxidant agents. We used three commercial chelators: DFO, deferiprone and 2.2’-dypyridyl, and three 8-hydroxyquinoline-based iron chelators: M30, 7MH and 7DH, and we evaluated their effects in vitro using a mesencephalic cell culture treated with the Parkinsonian toxin MPP+ and in vivo using the MPTP mouse model. All chelators tested promoted the emergence of new tyrosine hydroxylase (TH)-positive processes, increased axodendritic tree length and protected cells against lipoperoxidation. Chelator treatment resulted in the generation of processes containing the presynaptic marker synaptophysin. The antioxidants N-acetylcysteine and dymetylthiourea also enhanced axodendritic tree recovery in vitro, an indication that reducing oxidative tone fosters neuritogenesis in MPP+-damaged neurons. Oral administration to mice of the M30 chelator for 14 days after MPTP treatment resulted in increased TH- and GIRK2-positive nigra cells and nigrostriatal fibers. Our results support a role for oral iron chelators as good candidates for the early treatment of PD, at stages of the disease where there is axodendritic tree retraction without neuronal death.

Treating Alzheimer's disease by targeting iron

“…Deferiprone is an orally available iron chelator that is currently in clinical use and has been shown to cross the BBB. In animal models of Parkinson's disease, it has been shown to improve motor performance (Aguirre et al, 2015;Ayton, Lei, Duce, et al, 2013;Ayton, Lei, et al, 2015;Devos et al, 2014;Dexter et al, 2011;Workman et al, 2015). Deferiprone is neuroprotective in neuronal culture models of Aβ toxicity (Molina-Holgado, Gaeta, Francis, Williams, & Hider, 2008;Part et al, 2015), and it has been shown to reduce Aβ burden and tau phosphorylation in a rabbit model of AD (Prasanthi et al, 2012).…”

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

“…7DH [112] 7MH [112] 8A [89] 8B [89] 8C [89] 8E [89] 8F [89] N-Acetylcysteine [113,114] ACPT-I [115] ADX88178 [116] Alaternin [117] Alvespimycin [118] AM-251 [119,120]…”

“…Creatine [179,180] Cudraflavone B [181] Curcumin [89,117,[182][183][184] Cyanidin [185,186] D-512 [187] D-607 (bipyridyl-D2R/D3R agonist hybrid) [12,188,189] DA-2 (8D) [12,89] DA-3 [12] DA-4 [12] Dabigatran etexilate [190] Dabrafenib [191] (S)-3,4-DCPG [115] Deferasirox [24] Deferricoprogen [192] Delphinidin [160,185,193,194] Demethoxycurcumin [195] Dendropanax morbifera active compound [196] Desferrioxamine (Desferoxamine, Desferal, DFO) [112] (S)-N-(3-(3,6-Dibromo-9H -carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [197] 4,5-O-Dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid derivatives (R1, R2, R3, R4, or R5 = caffeoyl) [198] Dihydromyricetin [199]…”

“…Imipramine [247] Isobavachalcone [248] Isochlorogenic acid [167] Isoquercetin (Isoquercitrin) [249] Kaempferol [128,160,193,194] Kaempferol, 3-O-a-l arabinofuranoside-7-O-a-l-rhamnopyranoside [214] KR33493 [250] Kukoamine [251] Lestaurtinib [164] Lipoic acid [252][253][254] Luteolin [128] LY354740 [115] M10 [24] M30 (VAR10303) [112,255] M99 [24] Macranthoin G [256] Magnesium lithospermate B [257] [160,193,194,267] [18F]MPPF [107] MSX-3 [268] Myricetin [128,269,270] Myricitrin [271] Naringenin [128,272] Naringin [117,273,274] Nicotinamide adenine dinucleotide phosphate (NADPH) [275,276] Nicotinamide mononucleotide [277] Nitecapone [278] Nordihydroguaiaretic [160,193,194] Oleuropein…”

Utility of susceptibility-weighted imaging in Parkinson’s disease and atypical Parkinsonian disorders

“…This is in line with the fact that the Fe2+/Fe3+ ratio shift to the Fe3+ in PD [ 59 , 60 ]. Iron chelators can protect neurons from death in vitro, and PD patients may benefit from the decrease in iron level [ 12 , 61 , 62 ]. Some researchers believe that a localized, elevated iron level is caused by the iron-chelated neuromelanin that is released from dead neurones injured by aggregation of alpha-synuclein [ 54 ].…”