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Why Have Clinical Trials of Antioxidants to Prevent Neurodegeneration Failed? - A Cellular Investigation of Novel Phenothiazine-Type Antioxidants Reveals Competing Objectives for Pharmaceutical Neuroprotection

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Abstract

Purpose

Only a fraction of the currently established low-molecular weight antioxidants exhibit cytoprotective activity in living cells, which is considered a prerequisite for their potential clinical usefulness in Parkinson’s disease or stroke. Post hoc structure-activity relationship analyses have predicted that increased lipophilicity and enhanced radical stabilization could contribute to such cytoprotective activity.

Methods

We have synthesized a series of novel phenothiazine-type antioxidants exhibiting systematic variation in their lipophilicity and radical stabilization. Phenothiazine was chosen as lead structure for its superior activity at baseline. The novel compounds were evaluated for their neuroprotective potency in cell culture, and for their primary molecular targets.

Results

Lipophilicity was associated with enhanced cytoprotective activity, but only to a certain threshold (logP ≈ 7). Benzannulation likewise produced improved cytoprotectants that exhibited very low EC50 values of ~8 nM in cultivated neuronal cells. Inhibition of global protein oxidation was the best molecular predictor of cytoprotective activity, followed by the inhibition of membrane protein autolysis. In contrast, the inhibition of lipid peroxidation in isolated brain lipids and the suppression of intracellular oxidant accumulation were poor predictors of cytoprotective activity, primarily as they misjudged the cellular advantage of high lipophilicity.

Conclusions

Lipophilicity, radical stabilization and molecular weight appear to form an uneasy triangle, in which a slightly faulty selection may readily abolish neuroprotective activity.

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Abbreviations

ABTS:

2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)

ASC:

Ascorbic acid; vitamin C

BCA:

Bicinchoninic acid

BHT:

Butylated hydroxytoluene

DCFA:

2′,7′-Dichlorofluorescin diacetate

DMEM:

Dulbecco’s modified Eagle medium

DNPH:

2,4-Dinitrophenylhydrazine

EBS:

Ebselen

EDA:

Edaravone

FCS:

Fetal calf serum

HT22:

Glutamate-sensitive murine hippocampal cells

LUMOr:

Lowest unoccupied molecular orbital of a radical

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetra-zolium bromide

NXY:

NXY-059; disufenton sodium

PI:

Propidium iodide

TBA:

Thiobarbituric acid

TBARS:

Thiobarbituric acid-reactive substances

TEAC:

Trolox equivalent antioxidative capacity

TOC:

α-Tocopherol; vitamin E

TROX:

Trolox; 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

U74389G:

Methyl tirilazad

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Dr. James V. Crivello for his generous contribution of compounds 8, 9 and 10. The authors declare that they have no conflicts of interest. This work was supported by the Neuro Graduate School and the Interdisciplinary Research Centre for Neurosciences of the University of Mainz, which are non-profit entities that had no role in the design, execution, interpretation, or publication of this study.

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Authors and Affiliations

  1. Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55099, Mainz, Germany

    Maike J. Ohlow, Selina Sohre, Matthias Granold & Bernd Moosmann

  2. Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, 55131, Mainz, Germany

    Maike J. Ohlow & Mathias Schreckenberger

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  1. Maike J. Ohlow
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  2. Selina Sohre
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Correspondence to Maike J. Ohlow or Bernd Moosmann.

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Ohlow, M.J., Sohre, S., Granold, M. et al. Why Have Clinical Trials of Antioxidants to Prevent Neurodegeneration Failed? - A Cellular Investigation of Novel Phenothiazine-Type Antioxidants Reveals Competing Objectives for Pharmaceutical Neuroprotection. Pharm Res 34, 378–393 (2017). https://doi.org/10.1007/s11095-016-2068-0

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