Lactoferrin ameliorates dopaminergic neurodegeneration and motor deficits in MPTP-treated mice.
Xu SF1, Zhang YH1, Wang S1, Pang ZQ1, Fan YG1, Li JY2, Wang ZY3, Guo C4.
Redox Biol. 2018 Dec 21;21:101090. doi: 10.1016/j.redox.2018.101090.
Abstract
Brain iron accumulation is common in patients with Parkinson's disease (PD). Iron chelators have been investigated for their ability to prevent neurodegenerative diseases with features of iron overload. Given the non-trivial side effects of classical
iron chelators, lactoferrin (Lf), a multifunctional iron-binding globular glycoprotein, was screened to identify novel neuroprotective pathways against dopaminergic neuronal impairment. We found that Lf substantially ameliorated PD-like motor dysfunction
in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. We further showed that Lf could alleviate MPTP-triggered apoptosis of DA neurons, neuroinflammation, and histological alterations. As expected, we also found
that Lf suppressed MPTP-induced excessive iron accumulation and the upregulation of divalent metal transporter (DMT1) and transferrin receptor (TFR), which is the main intracellular iron regulation protein, and subsequently improved the activity of
several antioxidant enzymes. We probed further and determined that the neuroprotection provided by Lf was involved in the upregulated levels of brain-derived neurotrophic factor (BDNF), hypoxia-inducible factor 1α (HIF-1α) and its downstream protein,
accompanied by the activation of extracellular regulated protein kinases (ERK) and cAMP response element binding protein (CREB), as well as decreased phosphorylation of c-Jun N-terminal kinase (JNK) and mitogen activated protein kinase (MAPK)/P38 kinase
in vitro and in vivo. Our findings suggest that Lf may be an alternative safe drug in ameliorating MPTP-induced brain abnormalities and movement disorder.

KEYWORDS:
Iron chelators; Lactoferrin; Motor dysfunction; Parkinson's disease

PMID: 30593976 DOI: 10.1016/j.redox.2018.101090
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Review Mol Neurobiol. 2021 Aug 23. doi: 10.1007/s12035-021-02516-5.
Toxic Feedback Loop Involving Iron, Reactive Oxygen Species, α-Synuclein and Neuromelanin in Parkinson's Disease and Intervention with Turmeric
Zuné Jansen van Rensburg 1, Shameemah Abrahams 1 2, Soraya Bardien 3 4, Colin Kenyon 5 6 7
PMID: 34426907 DOI: 10.1007/s12035-021-02516-5
Abstract
Parkinson's disease (PD) is a movement disorder associated with severe loss of mainly dopaminergic neurons in the substantia nigra. Pathological hallmarks include Lewy bodies, and loss of neuromelanin, due to degeneration of neuromelanin-containing
dopaminergic neurons. Despite being described over 200 years ago, the etiology of PD remains unknown. Here, we highlight the roles of reactive oxygen species (ROS), iron, alpha synuclein (α-syn) and neuromelanin in a toxic feedback loop culminating in
neuronal death and spread of the disease. Dopaminergic neurons are particularly vulnerable due to decreased antioxidant concentration with aging, constant exposure to ROS and presence of neurotoxic compounds (e.g. ortho-quinones). ROS and iron increase
each other's levels, creating a state of oxidative stress. α-Syn aggregation is influenced by ROS and iron but also increases ROS and iron via its induced mitochondrial dysfunction and ferric-reductase activity. Neuromelanin's binding affinity is
affected by increased ROS and iron. Furthermore, during neuronal death, neuromelanin is degraded in the extracellular space, releasing its bound toxins. This cycle of events continues to neighboring neurons in the form of a toxic loop, causing PD
pathology. The increase in ROS and iron may be an important target for therapies to disrupt this toxic loop, and therefore diets rich in certain 'nutraceuticals' may be beneficial. Turmeric is an attractive candidate, as it is known to have anti-oxidant
and iron chelating properties. More studies are needed to test this theory and if validated, this would be a step towards development of lifestyle-based therapeutic modalities to complement existing PD treatments.

Keywords: Alpha-synuclein; Iron; Neuromelanin; Parkinson’s disease; Reactive oxygen species; Toxic feedback loop.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.


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