Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Abstract

Summary.To elucidate the neuroprotective effects of the iron chelator desferrioxamine (DFO) and the antioxidant vitamin E on excessive ironinduced free radical damage, a chronic iron-loaded mice model was established. The relationship between striatal iron content, oxidized to reduced glutathione ratio, hydroxyl radical ('OH) levels and dopamine concentrations were observed in DFO or vitamin E pretreated iron-loaded/1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. The results demonstrated that both DFO and vitamin E inhibit the iron accumulation and thus reverses the increase in oxidized glutathione (GSSG), oxidized to reduced glutathione ratios, "OH and lipid peroxidation levels. The striatal dopamine concentration was elevated to normal value. Our data suggested that: (1) iron may induce neuronal damage and thus excessive iron in the brain may contribute to the neuronal loss in PD; (2) iron chelators and antioxidants may serve as potential therapeutic agents in retarding the progression of neurodegeneration.

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

“…8B, *, p Ͻ 0.05 between control/control and DHB/control; #, p Ͻ 0.05 between control/MPP ϩ and DHB/MPP ϩ ). Although iron chelators have been shown to be protective against MPP ϩ neurotoxicity (24,40), it was determined that PHD inhibition by DHB was also able to attenuate cell death associated with a toxic concentration of MPP ϩ (Fig. 8C, *, p Ͻ 0.005 between control/control and control/MPP ϩ ; ∧, p Ͻ 0.001 between control/ MPP ϩ and DHB/MPP ϩ ), results that parallel those observed in vivo (Fig.…”

“…4B). Although, as previously demonstrated (24,25), MPTP treatment alone was found to result in a significant increase in striatal iron levels, this was found to be abolished in the presence of DHB pretreatment. An absence of alterations in iron levels in the cerebellum confirms the regional specificity of the effects of MPTP neurotoxicity on the nigrostriatal system in vivo.…”

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

“…103 A similar effect was shown in the MPTP model. 104 Clioquinolpretreated MPTP mice had total substantia nigra iron levels decreased 30% when compared to control animals. 105 The iron levels obtained after clioquinol pretreatment were below known toxic levels.…”

“…Although animal experiments have demonstrated effectiveness in PD, 101,103,104 AD, 83,91 and MS, [117][118][119][120] iron chelation therapy in chronic brain disorders in humans has not been studied extensively. A few studies have been successful, 24 whereas others have not.…”

Ironing out Parkinson's disease: is therapeutic treatment with iron chelators a real possibility?

“…It is a powerful chelating agent which displaces iron from neuromelanin. When administered in combination with alpha-tocopherol, it was found to inhibit iron accumulation and oxidative stress and to increase dopamine concentrations to normal values in the MPTP animal model (Lan & Jiang, 1997b). Besides iron chelation, desferrioxamine has also been suggested to have antioxidant properties and a capacity to activate mitochondrial complex I (Glinka et al ., 1998) which is seen to be systemically inhibited in PD patients.…”