Objective/Rationale:
We will test two novel, orally bioavailable, brain-penetrant iron chelators in a pre-clinical model of Parkinson’s disease (PD) for their ability to reduce labile iron-associated oxidative stress and neurodegeneration. Free iron that accumulates in the substantia nigra of the brain in Parkinson’s patients drives oxidative stress, leading to selective destruction of dopaminergic neurons, the brain cells that produce dopamine. Thus the removal of excess labile iron from the substantia nigra, or its binding into non-toxic complexes, is a rational target in PD.
Project Description:
The two iron chelators will be studied in a chronic, toxin-induced pre-clinical model of PD, which features selective degeneration of dopaminergic neurons, brain iron accumulation, and oxidative stress. Improvement in motor function in response to treatment will be assessed using multiple behavioural tests. Changes in levels of dopamine, free iron levels in the substantia nigra and markers of oxidative stress, and protective effects on dopaminergic neurons will be examined and correlated with behavioral outcomes. The therapeutic effect of these novel compounds will be compared to deferiprone, a structurally related iron chelator with neuroprotective properties in pre-clinical models of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Existing treatments manage the early motor symptoms of PD, mainly through replacement of the body’s own dopamine supply. However, these drugs do not provide a cure or slow disease progression, and they become ineffective at later stages of the condition, when dopaminergic neurons have been severely depleted. Our approach to PD treatment has the potential to prevent the progressive loss of dopaminergic neurons and therefore to either arrest or delay the progression of the disease.
Anticipated Outcome:
We expect that demonstrating of efficacy of our iron chelators in an established pre-clinical model of PD will allow us to move quickly into studies that are ultimately necessary to make an effective drug available to patients. The project will provide valuable pharmacological data to help design appropriate clinical trials and to prove the concept of a new approach to PD treatment. We also hope to progress understanding of the role of brain iron and mechanisms of modulating it as an approach to disease-modifying therapy.
Final Outcome
Deferiprone, an orally bioavailable, brain-penetrant iron chelator, has been shown to significantly reduce motor behavior deficit in a chemically induced pre-clinical model of Parkinson’s disease (PD). Deferiprone works by removal and redistribution of excess iron in the area of the brain known as the substantia nigra (SN). Accumulation of, iron in the SN is believed to contribute to the adverse effects of PD, and its removal prevents iron-mediated tissue damage arising through free radical formation and oxidative stress.
Following on our studies of deferiprone, we tested the two most promising, novel iron chelators were examined in a pre-clinical model of PD for their ability to oppose loss of muscle control and to protect against degeneration of the dopaminergic neurons. Our studies demonstrated that the new compounds improved nerve-muscle function, normalized production and metabolism of dopamine, and reduced oxidative damage to the brain. The effects of these compounds increased reliably with increasing dose, and both performed better than deferiprone. One of the novel iron chelators conserved dopamine nerve cells and, in particular, their communication with the striatum, the part of the brain that coordinates motivation and movement, raising a possibility that it might have a directly protective effect on neurons.