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Neuroprotection and Neurorestoration of Nigra Striatal Dopamine Neurons by Novel Multitarget Drugs, M30

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Handbook of Neurotoxicity

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Abstract

Iron-dependent oxidative stress, elevated levels of iron and of monoamine oxidase (MAO)-B activity, and depletion of antioxidants in the brain may be major pathogenic factors in Parkinson’s disease and related neurodegenerative diseases. Therefore, several novel multifunctional brain-permeable iron chelators-MAO inhibitors have been developed, aimed for prevention and treatment of Parkinson’s disease (PD). These potential drugs were synthesized as hybrid molecules containing brain-permeable VK28-derived iron chelator moiety, on the one hand, and N-propargylamine-derived MAO inhibitor moiety, on the other hand. The hypothesis underlying the design of such drugs was that it is possible that targeting multiple brain substrates might develop additive or synergistic positive actions. Based on previous studies, where several drugs were screened in-vitro, in the present study, selected drugs were further investigated ex vivo and in vivo. Initially, characterized several combined molecules ex vivo, in order to determine which of the molecules were most potent, both as iron chelators and MAO inhibitors. Based on these findings, the hybrid molecule M30 is brain-permeable, potent irreversible MAO-A/B inhibitor and but not in the liver or small intestine. This effect was shown following a single and chronic drug administration, regardless of whether the drug was administered intraperitoneally or orally. In the rat model, M30 was shown to induce only limited tyramine-induced blood pressure potentiation, increasing the pressor response as compared with tranylcypromine, suggesting that M30 would not lead to a severe side effect common to non-selective MAO-A/B inhibitors, known as the “cheese effect,” characterized by life-threatening hypertension. M30 has both neuroprotective and neurorestorative activities in MPTP and other models of PD. The neuroprotective activity depends on activation of Bcl2 family proteins and downregulation of Bax proteins. Neurorestorative activity has been attributed to upregulation of HIF (hypoxia-inducing factor) which regulated the neurotrophins BDNF, GDNF, NGF, VEGF, and erythropoietin.

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Abbreviations

5-HIAA:

5-hydroxyindolacetic acid

5-HT:

Serotonin

6-OHDA:

6-hydroxydopamine

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

Aβ:

β-amyloid

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

BSA:

Bovine serum albumin

COMT:

Catechol-o-methyltransferase

DA:

Dopamine

DG:

Dentate gyrus

DNA:

Deoxyribonucleic acid

DOPA:

3,4dihydroxyphenylalanine

DOPAC:

3,4 dihydroxyphenylacetic acid

DTT:

Dithiothreitol

EDTA:

Ethylenediaminetetraacetic acid

EGCG:

Epigallocatechin-3-gallate

GDNF:

Glial cell line-derived neurotrophic factor

GSH:

Reduced glutathione

H2O2:

Hydrogen peroxide

HPLC:

High-pressure liquid chromatography

HVA:

Homovanillic acid

i.c.v.:

Intraventricularly

i.p.:

Intraperitoneal

l OS:

Oxidative stress

LPO:

Iron-induced lipid peroxidation assay

MAO:

Monoamine oxidase

Mg:

Milligram

min:

Minute

mM:

Millimolar

MPP+:

1-methyl-4-pyridinium

MPTP:

N-methyl 4 phenyl 1,2,3,6 tetrahydropyridine

mRNA:

messenger RNA

NA:

noradrenaline

NGF:

nerve growth factor

OH•:

Hydroxyl radical

p.o.:

Per os

PBS:

Phosphate buffered saline

PC12:

Pheochromocytoma cells

PD:

Parkinson’s disease

PEA:

Phenylethylamine

PKC:

Protein kinase C

ROS:

Reactive oxygen species

SDS:

Sodium dodecyl sulfate

SGZ:

Sub granular zone

SN:

Substantia nigra

SNPC:

Substantia nigra pars compacta

SVZ:

Subventricular zone

TCP:

Tranylcypromine

TH:

Tyrosine hydroxylase

μg:

Microgram

μl:

Microliter

VEGF:

Vascular endothelium growth factor

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  1. Shunit Ben Ari

    Present address: Research Authoreties, Israel Institute of Technology. Technion City, Haifa, Israel

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    Moussa B. H. Youdim

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    Richard M. Kostrzewa

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Ben Ari, S., Youdim, M.B.H. (2021). Neuroprotection and Neurorestoration of Nigra Striatal Dopamine Neurons by Novel Multitarget Drugs, M30. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_211-1

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