I posted this paper when it was published but ATH never told us about it. However, it is an important paper, IMO.

Here are the main results:

PBT434 has no cytotoxic effects on brain microvascular endothelial cells

PBT434 is rapidly taken up and trafficked across the hBMVEC barrier

PBT434, unlike bipyridyl, does not limit the intracellular availability of labile iron

55Fe2+ uptake is inhibited by complexation with PBT434

PBT434 stimulates Fpn-dependent 55Fe2+ efflux

"In summary, we provide in vitro evidence for the trafficking of PBT434 across the BBB and into the brain interstitium consistent with the results of early phase clinical trials. Additionally, we show that while PBT434 has moderate effects on the LIP and regulation of downstream iron-dependent protein expression, it does not significantly interrupt normal cell physiology, unlike high affinity iron chelators. In addition, PBT434 is able to bind and redistribute extracellular ionic Fe2+, limiting the downstream oxidative stress associated with this pro-oxidant and its role in cytotoxic protein aggregation. This novel mechanism of action provides a compelling case for the continued development of PBT434 as a therapeutic agent in neurodegenerative diseases correlated with metal accumulation."


This is an in vitro study, but now with all the other ATH434 papers and the progress in understanding PD and MSA, this info becomes even more important, IMO.

Here is the abstract of this free paper:

PLoS One

. 2021 Jul 26;16(7):e0254794.

doi: 10.1371/journal.pone.0254794. eCollection 2021.

The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells

Danielle K Bailey ¹, Whitney Clark ¹, Daniel J Kosman ¹

Affiliations expand

• PMID: 34310628

PMCID: PMC8312958 DOI: 10.1371/journal.pone.0254794

Abstract

Iron and other transition metals, such as copper and manganese, are essential for supporting brain function, yet over-accumulation is cytotoxic. This over-accumulation of metals, particularly iron, is common to several neurological disorders; these include Alzheimer's disease, Parkinson's disease, Friedrich's ataxia and other disorders presenting with neurodegeneration and associated brain iron accumulation. The management of iron flux by the blood-brain barrier provides the first line of defense against the over-accumulation of iron in normal physiology and in these pathological conditions. In this study, we determined that the iron chelator PBT434, which is currently being developed for treatment of Parkinson's disease and multiple system atrophy, modulates the uptake of iron by human brain microvascular endothelial cells (hBMVEC) by chelation of extracellular Fe2+. Treatment of hBMVEC with PBT434 results in an increase in the abundance of the transcripts for transferrin receptor (TfR) and ceruloplasmin (Cp). Western blot and ELISA analyses reveal a corresponding increase in the proteins as well. Within the cell, PBT434 increases the detectable level of chelatable, labile Fe2+; data indicate that this Fe2+ is released from ferritin. In addition, PBT434 potentiates iron efflux likely due to the increase in cytosolic ferrous iron, the substrate for the iron exporter, ferroportin. PBT434 equilibrates rapidly and bi-directionally across an hBMVEC blood-brain barrier. These results indicate that the PBT434-iron complex is not substrate for hBMVEC uptake and thus support a model in which PBT434 would chelate interstitial iron and inhibit re-uptake of iron by endothelial cells of the blood-brain barrier, as well as inhibit its uptake by the other cells of the neurovascular unit. Overall, this presents a novel and promising mechanism for therapeutic iron chelation.