Iron accumulation in Patients with Parkinson’s Disease

Mohammed Ali Chehade, Xin Yi Huang, Brianna Kispal, Jae Eun Shim

PHM 142University of Toronto

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

What is Parkinson’s Disease?

Parkinson’s disease is a progressive disorder of the nervous system that involves the neurodegeneration of dopaminergic neurons of the substantia nigra.

Since it is a progressive disorder, symptoms continue and worsen over time.

It is the second most common neurodegenerative disease, behind Alzheimer’s, which affects approximately 1% of the population.

Symptoms Associated with Parkinson’s Disease

Symptoms at Different Stages of Parkinson’s Disease

Stage 1: Early Stage Stage 2: Moderate Stage 3: Advanced

Tremors, joint pain, weakness, and fatigue

Slow movement, stiff muscles, poor coordination, problems with posture

and balance (speech and writing problems)

Muscle stiffness and severe tremors, decrease in self-care function and

wheelchair usage

Causes of PDThe cause or causes of Parkinson’s disease is not known, however, there are many current theories.

Increased oxidative stress in dopaminergic neurons

DOPAMINEDOPAC HVA

H2O2 + Fe2+ OH* + OH- + Fe3+

MAO, FAD

Iron accumulation in Substantia Nigra(SN)PD results from the death of dopaminergic neurons in the substantia nigra. SN has constitutively high levels of iron and dopamine, and iron levels increase with age. In patients with PD, there is pathological iron accumulation.

Iron accumulation in Substantia Nigra(SN)

Potential causes of iron accumulation are due to iron homeostasis imbalance demonstrated in PD rat models. DMT1 (an iron import channel) is up-regulated and ferroportin 1 (an iron export channel) is down-regulated:

• ferroportin 1 mRNA has IRE on 5’ end; DMT1 mRNA has IRE on 3’ end• increased ROS levels activate IRPs, which then bind IREs• IRP-IRE complex bound on ferroportin 1 mRNA increases translation while IRP-IRE complex bound on

DMT1 mRNA decreases translation• increased iron import and decreased iron export lead to increased intracellular iron

Another potential pathway is ceruloplasmin (CP) dysfunction, which facilitates iron export by oxidizing ferrous (Fe2+) to ferric (Fe3+) iron. CP dysfunction has been observed in the SN of PD patients, and this may be due to inactivation of CP by ROS. Studies have shown that CP-knockout mice develop PD within 6 months.

How do high levels of iron confer neurotoxicity?

Iron as a cause of PD

Increased intracellular iron saturates neuromelanin, an iron chelator in substantia nigra dopaminergic neurons. Overwhelming these iron chelators eventually lead to increased free iron intracellular iron and increased oxidative stress, and eventual cell death. This releases neuromelanin extracellularly, and can activate microglia (macrophages in the CNS) and cause neuroinflammation.

inflammatory cytokines also affect iron homeostasis in astrocytes and microglia:• proinflammatory TNF-alpha increases iron uptake and retention in astrocytes and microglia• anti-inflammatory TGF-beta1 promotes iron efflux in astrocytes and iron retention in microglia

Iron homeostasis imbalance as a primary cause of PD is controversial. There are studies showing conflicting results. Some observed iron storage in SN at various stages of PD, while other studies did not observe nigral iron accumulation.

Iron as a cause of PD

• Therefore, Iron chelation may be used as a means of PD treatment

Kaur, D et al. Neuron 37(6), 899-909 (March 2003)

Effects of Acute MPTP Administration on Dopaminergic SN Neuronal Cell Number in pTH-Ferritin Transgenics versus Wild-Type.

Possible iron chelator for PD- Deferiprone

• Iron chelators: Inhibition of Fe2+ reduction, protection against damages from the reduction•Possible problem? Systemic chelation vs Cellular specific chelation

• Deferiprone(DFP): Phase II clinical research• Benefits: additional antioxidant properties for comprehensive mode of action.

effective cellular specific chelation.

Mounsey, R. and Teismann, P. Int J Cell Biol 2012, (March 2012)Hoffbrand, A., Taher, A., Cappellini, M. Blood 120(18), 3657-3669 (Novermber 2012)

Targeting Chelatable Iron as a Therapeutic Modality in Parkinson's Disease

Partial recovery of dopaminergic cells within the SN through oral chelator Deferiprone(DFP)

Partial recovery of dopamine through DFP treatment

Reduced oxidation products of DNA

Devos, D et al. Antioxid Redox Signal 21(2), 195–210 (July 2014)

Human Iron Chelation Study - DeferiproneGrolez et al. (2015)

● 40 PD patients recruited for an 18 month clinical trial

● given a 30mg/kg daily dose of DFP

● substantia nigra (SN) iron levels and disease progression were assessed

● Results: DFP resulted in lower SN iron levels and reduced disease progression

● additionally, ceruloplasmin (CP) activity was increased

● *D544E CP polymorphism responded better to chelation

Implication to pharmacists

Discovery of pharmacological treatment rather than symptom management!

Iron chelators(ie DeferipronePD)

Summary*Parkinson’s disease is a progressive disorder of the nervous system that involves the neurodegeneration of dopaminergic neurons of the substantia nigra.

*Common causes of Parkinson’s disease include: genetics, oxidative stress, disturbances to synaptic function, environmental factors, presence of Lewy bodies, and age.

*Dopamine metabolism creates oxidative stress as H2O2 is produced as a byproduct.*Iron accumulation in Parkinson’s disease is a result of iron homeostasis imbalance where DMT1 is over-expressed and ferroportin 1 is under-expressed.

*High levels of iron saturates neuromelanin and increases oxidative stress. Neural cells are killed and neuromelanin is released in the extracellular environment. Free neuromelanin causes microglia activation and neuroinflammation, which can further disturb iron homeostasis.

*Iron chelation can be a treatment for Parkinson’s Disease (currently under investigation)*Deferiprone(DFP): Iron chelator that reduces free iron and binds to the ferric iron. It crosses blood brain barrier and maintains iron homeostasis in the body which makes it viable drug for parkinson’s disease.

*Preliminary patient studies with DFP have shown promising reductions in iron levels of the substantia nigra and improved motor function in Parkinson’s disease patients

ReferencesAyton, S et al. "Iron Accumulation Confers Neurotoxicity to a Vulnerable Population of Nigral Neurons: Implications for Parkinson's Disease." Molecular Neurodegeneration 9 (2014): 27. Bharath, Srinivas, et al. "Glutathione, Iron and Parkinson's Disease." Biochemical Pharmacology 64 (2002): 1037-048.Calne, Donald B. "The Treatment of Parkinson's Disease." Drug Therapy 329.14 (1993): 1021-027.

Devos, D et al. “Targeting chelatable iron as a therapeutic modality in Parkinson's disease.” Antioxidant & Redox Signaling 21.2 (2014): 195–210.

Hoffbrand, A., Taher, A., and Cappellini, M. “How I treat transfusional iron overload.” Blood 120.18 (2012): 3657-3669.Jiang, H et al. "Up-Regulation of Divalent Metal Transporter 1 in 6-Hydroxydopamine Intoxication is IRE/IRP Dependent." Cell research 20.3 (2010): 345-56.

Kaur, D et al. “Genetic or Pharmacological Iron Chelation Prevents MPTP-Induced Neurotoxicity In Vivo: A Novel Therapy for Parkinson’s Disease.” Neuron 37(6) (2013):899-909 .Meiser, J et al. "Complexity of Dopamine Metabolism." Cell Communication and Signaling 11.1 (2013): 34.

Mounsey, R. and Teismann, P. “Chelators in the treatment of iron accumulation in Parkinson’s disease.” International Journal of Cell Biology 2012 (2012).Song, N et al. "Ferroportin 1 but Not Hephaestin Contributes to Iron Accumulation in a Cell Model of Parkinson's Disease." Free Radical Biology and Medicine 48.2 (2010): 332-41.

"What Is Parkinson's Disease?" Parkinson's Disease Foundation. Web. 31 Oct. 2015.Grolez, G et al. "Ceruloplasmin activity and iron chelation treatment of patients with Parkinson’s disease." BMC Neurology 15:74 (2015).