Editors' ChoiceNeurodegenerative Disease

Desferrioxamine passes the sniff test

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Science Translational Medicine  06 Apr 2016:
Vol. 8, Issue 333, pp. 333ec55
DOI: 10.1126/scitranslmed.aaf6933

The iron chelator desferrioxamine (DFO) has received attention recently as a potential therapeutic for diseases such as Parkinson’s and Alzheimer’s, in which iron accumulation in the brain is thought to be pathogenic. As DFO may cause widespread iron depletion when administered systemically, intranasal application is an attractive route for focused delivery of DFO to the brain via the olfactory neurons. New evidence from Guo et al. supports intranasal DFO delivery as an effective approach to block neurodegeneration in a mouse model of Parkinson’s disease (PD).

Intranasal treatment with DFO every other day for a period of 4 weeks attenuated the disease-related loss of dopaminergic neurons in the substantia nigra of mice induced by a chemical called MPTP and characterized by accumulation of iron in nigral and striatal neurons. Such iron accumulation may be due to up-regulation of a metal transporter and the transferrin receptor. DFO alleviated iron uptake into neurons in these regions and also limited metal transporter and transferrin receptor expression following induction of neurodegeneration with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mechanistically, DFO may promote neuronal recovery from MPTP-related toxicity through the stabilization and activation of hypoxia-inducible factor–1α (HIF-1α) and, in turn, up-regulation of HIF-1α–responsive genes. Decreased stress-responsive JNK activation and a decreased ratio of proapoptotic Bax to antiapoptotic Bcl2 were also observed following DFO treatment, which might contribute to its neuroprotective effects. DFO also ameliorated locomotor deficits caused by MPTP and associated with dopamine neuron degeneration.

As the MPTP animal model recapitulates the elevated iron concentrations seen in the substantia nigra of PD patients, it is a useful preclinical model for assessing intranasal delivery of iron chelators such as DFO. The study suggests that restoring iron homeostasis in the brain can prevent neurodegeneration in these mice. Yet, more work is needed to determine whether iron accumulation plays a primary role in the loss of dopamine neurons in PD patients, since this will ultimately determine the therapeutic potential of DFO, regardless of how it is administered.

C. Guo et al., Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice. Exp. Neurol. 10.1016/j.expneurol.2016.03.016 (2016). [Abstract]

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