Lactoferrin protects against iron dysregulation, oxidative stress, and apoptosis in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice.

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Its pathological features are dopaminergic neuronal death in the substantia nigra (SN), and significant reduction in dopamine (DA) content in the striatum. A large number of studies have found an increase in iron levels in PD patients and animal models, which suggested that brain iron metabolism dysfunction played a key role in the pathogenesis of PD. Lactoferrin (Lf) is a non-heme iron-binding glycoprotein belonging to the transferrin family, entering the cell membrane via a lactoferrin receptor-mediated pathway. Lf exists mainly in two forms: iron-free-lactoferrin (apo-Lf) and iron-saturated-lactoferrin (holo-Lf). Our previous studies found thatapo-Lf and holo-Lf exert neuroprotective effects against 1-methyl-4-phenylpyridinium toxicity in ventral mesencephalon neurons in vitro. This study aimed to further investigate whether two different forms of Lf have neuroprotective effects in vivo, and to examine their mechanisms, so as to provide an experimental basis for finding new therapeutic strategies against PD. In the central nervous system, Lf antagonized 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced DA depletion in the striatum, iron deposition, oxidative, and apoptotic processes in the SN. Lf treatment down-regulated iron import protein divalent metal transporter1 and up-regulated iron export protein ferroportin1, attenuating MPTP-induced accumulation of nigral iron level. In the peripheral system, Lf alleviated MPTP-induced increases in serum iron and ferritin, and decreases in serum total iron-binding capacity, loss of spleen weight, and reduction in spleen iron content. The results indicate that Lf has a neuroprotective effect on MPTP-induced PD model mice, and its mechanism may be related to anti-iron dysregulation, anti-oxidative stress, and anti-apoptosis, with apo-Lf showing greater efficacy. Therefore, Lf might be a promising therapeutic substance for PD. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.