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Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice
Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, Smith E, Ortori CA et al.. Brain : a journal of neurology, 2017-06-01
Topic: Brain proteins, microglia and lab models
See Mercado and Hetz (doi:10.1093/brain/awx107) for a scientific commentary on this article.Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo . Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.
Key findings
- Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival.
Why it matters
In mouse models of neurodegeneration, two existing drugs, trazodone and dibenzoylmethane, restored memory deficits, prevented neurodegeneration and prolonged survival by acting on a pathway overactivated in Alzheimer's disease. These are early animal findings, so it is not yet known whether these drugs help people with Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 53/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | 4 / 4 | Brain: journal h-index 503 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mice”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 294 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 26.7 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 4 / 6 | Cited 16.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 3 / 4 | Cited 57 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Giovanna R. Mallucci: h-index 36 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Cambridge: institution h-index 1,973 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28430857) |
| Free to read | 2 / 2 | Free to read |
| Total | 53 / 100 | — |
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Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Halliday, M., Radford, H., Zents, K. A. M., Molloy, C., Moreno, J. A., Verity, N. C., et al. (2017). Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain : a journal of neurology. https://doi.org/10.1093/brain/awx074
Vancouver
Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain : a journal of neurology. 2017. doi:10.1093/brain/awx074. PMID: 28430857.
BibTeX
@article{halliday2017-28430857,
author = {Halliday, M. and Radford, H. and Zents, K. A. M. and Molloy, C. and Moreno, J. A. and Verity, N. C. and Smith, E. and Ortori, C. A. and others},
title = {{Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice}},
journal = {Brain : a journal of neurology},
year = {2017},
doi = {10.1093/brain/awx074},
pmid = {28430857},
url = {https://doi.org/10.1093/brain/awx074}
}
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