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Melatonin Analogues Potently Inhibit MAO-B and Protect PC12 Cells against Oxidative Stress

Published on Friday, 29 October 2021

Abstract

Monoamine oxidase B (MAO-B) metabolizes dopamine and plays an important role in oxidative stress by altering the redox state of neuronal and glial cells.

MAO-B inhibitors are a promising therapeutical approach for Parkinson's disease (PD). Herein, 24 melatonin analogues (3a-x) were synthesized as novel MAO-B inhibitors with the potential to counteract oxidative stress in neuronal PC12 cells.

Structure elucidation, characterization, and purity of the synthesized compounds were performed using 1H-NMR, 13C-NMR, HRMS, and HPLC. At 10 µM, 12 compounds showed >50% MAO-B inhibition. Among them, compounds 3n, 3r, and 3u-w showed >70% inhibition of MAO-B and IC50 values of 1.41, 0.91, 1.20, 0.66, and 2.41 µM, respectively.

When compared with the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), compounds 3n, 3r, 3u, and 3v demonstrated better selectivity indices (SI > 71, 109, 83, and 151, respectively).

Furthermore, compounds 3n and 3r exhibited safe neurotoxicity profiles in PC12 cells and reversed 6-OHDA- and rotenone-induced neuronal oxidative stress.

Both compounds significantly up-regulated the expression of the anti-oxidant enzyme, heme oxygenase (HO)-1. Treatment with Zn(II)-protoporphyrin IX (ZnPP), a selective HO-1 inhibitor, abolished the neuroprotective effects of the tested compounds, suggesting a critical role of HO-1 up-regulation. Both compounds increased the nuclear translocation of Nrf2, which is a key regulator of the antioxidative response.

Taken together, these data show that compounds 3n and 3r could be further exploited for their multi-targeted role in oxidative stress-related PD therapy.

NOTE: This publication cites (Ref. N.54): Di Bella G., Mascia F., Gualano L., Di Bella L. - Melatonin anticancer effect: review. Int J Mol Sci. 2013;14:2410–2430.

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About this publication.

- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Vitamin C/Ascorbic Acid, 2–4 grams, twice a day orally);

- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);

- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);