Lactoferrin ameliorates dopaminergic neurodegeneration and motor deficits in MPTP-treated mice

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.

Potential role of lactoferrin in early diagnostics and treatment of Parkinson disease

“…These results are confirmed by other studies in which LF protected a culture of dopaminergic neurons from toxic effects of MPTP [67] or mice [69,70] against the MPTP-induced neurodegeneration. In MPTP-treated mice the level of divalent metal transporter 1 in striatum became significantly higher in comparison with the control group, but after LF treatment it was substantially decreased [69]. The following scheme summarizes the effects of LF treatment in PD animal models, differing in the pathogenetic links affected.…”

“…Indeed, intraperitoneal and nasal administration of LF to rodents protects the animals against neurodegeneration, including the rotenone-induced model of PD in rats [42]. These results are confirmed by other studies in which LF protected a culture of dopaminergic neurons from toxic effects of MPTP [67] or mice [69,70] against the MPTP-induced neurodegeneration. In MPTP-treated mice the level of divalent metal transporter 1 in striatum became significantly higher in comparison with the control group, but after LF treatment it was substantially decreased [69].…”

Decreased salivary lactoferrin levels are specific to Alzheimer's disease

“…Lf antioxidant activities have also been described in PD experimental models in which this protein was able to prevent oxidative stress and to upregulate the expression of antioxidant enzymes. Simultaneously, the expression of glial markers and proinflammatory cytokines were found reduced 51 , 52 . Therefore, a boosting effect of Lf may be potentially observed when this protein exerts its antioxidant properties through its iron scavenging abilities and this effect would potentiate the immune response [53] .…”

Iron in Neurodegeneration – Cause or Consequence?

“…In MPTP mice modeling PD, administration of LF results in reduction of MPTP-induced iron accumulation via suppressed upregulation of DMT1 and TfR. Furthermore, neuroprotection is mediated by an increase in BDNF and HIF-1α with downstream activation of ERK/1/2-CREB pathway (Xu et al, 2018). In addition, LF receptors are found at the BBB, therefore LF may also be utilized as carrier for iron chelators that would otherwise be excluded from CNS.…”