A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson’s Disease

Abstract

Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson's disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP + ). MPP+'s mechanism of toxicity relates to its ability to inhibit complex-I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes, hence the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, while CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria.We extend these findings by characterising the drug's interactive effects at the METC level.CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+ -induced upregulated expression of Hypoxia Inducible Factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agent.

Iron imbalance in neurodegeneration

“…These disappointing results are stimulating new therapeutic approaches aimed at limiting iron overload and its consequences. Compounds with multiple functions that can block several steps of the neurodegenerative process are being tested in preclinical model [ 189 , 190 ]. In addition, advances in the knowledge of ferroptosis have led to the identification of numerous inhibitors of this process that can be considered novel potential pharmacological targets for neuroprotective strategies [ 191 ].…”

Hypoxia Sensing and Responses in Parkinson’s Disease

“…First, in various cellular and animal models of PD (toxin and α-synuclein-overexpression models), pharmacological strategies that enhance HIF stability/activity (e.g., using HIFinducing iron chelators like deferoxamine, the HIF-activator agmantin, prolyl hydroxylase inhibitors like FG-4592, or the HIF-1α-transcription-enhancing compound albendazole) have been shown to be beneficial [74][75][76][77][78][79][80]. Second, responses to hypoxia can be improved by activation of delta opioid receptors, which have been shown to blunt alpha-synuclein expression and toxicity in a cellular toxin model of PD [81].…”