| Title |
Why Have Clinical Trials of Antioxidants to Prevent Neurodegeneration Failed? - A Cellular Investigation of Novel Phenothiazine-Type Antioxidants Reveals Competing Objectives for Pharmaceutical Neuroprotection
|
|---|---|
| Published in |
Pharmaceutical Research, November 2016
|
| DOI | 10.1007/s11095-016-2068-0 |
| Pubmed ID | |
| Authors |
Maike J. Ohlow, Selina Sohre, Matthias Granold, Mathias Schreckenberger, Bernd Moosmann |
| Abstract |
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. 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. 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. Lipophilicity, radical stabilization and molecular weight appear to form an uneasy triangle, in which a slightly faulty selection may readily abolish neuroprotective activity. |
X Demographics
The data shown below were collected from the profile of 1 X user who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 22 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 22 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 5 | 23% |
| Student > Master | 4 | 18% |
| Student > Doctoral Student | 3 | 14% |
| Student > Postgraduate | 2 | 9% |
| Researcher | 2 | 9% |
| Other | 1 | 5% |
| Unknown | 5 | 23% |
| Readers by discipline | Count | As % |
|---|---|---|
| Chemistry | 5 | 23% |
| Biochemistry, Genetics and Molecular Biology | 3 | 14% |
| Agricultural and Biological Sciences | 3 | 14% |
| Medicine and Dentistry | 3 | 14% |
| Neuroscience | 1 | 5% |
| Other | 1 | 5% |
| Unknown | 6 | 27% |
Attention Score in Context
This research output has an Altmetric Attention Score of 13. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 03 October 2023.
All research outputs
#2,639,818
of 24,580,204 outputs
Outputs from Pharmaceutical Research
#120
of 2,959 outputs
Outputs of similar age
#51,391
of 426,457 outputs
Outputs of similar age from Pharmaceutical Research
#2
of 27 outputs
Altmetric has tracked 24,580,204 research outputs across all sources so far. Compared to these this one has done well and is in the 89th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 2,959 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.4. This one has done particularly well, scoring higher than 95% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 426,457 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 87% of its contemporaries.
We're also able to compare this research output to 27 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 92% of its contemporaries.