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Cited by 293Endoplasmic Reticulum Stress and DiseaseAlzheimer's disease research and treatmentsRNA and protein synthesis mechanisms

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Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice

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Halliday, Mark, Radford, Helois, Zents, Karlijn A. M., Molloy, Collin, Moreno, Julie A., Verity, Nicholas C., Smith, Ewan, Ortori, Catharine A., Barrett, David A., Bushell, Martin, Mallucci, Giovanna R.·2017·Brain
DOI 10.1093/brain/awx074PMC PMC5445255
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Abstract

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.

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  • In the MAPT P301L mouse model of tauopathy, trazodone use was associated with less memory deficits, preserved hippocampal neuronal counts, delayed gross brain atrophy, and prolonged survival.

    “in the MAPT P301L mouse model of tauopathy, trazodone use was associated with less memory deficits, preserved hippocampal neuronal counts, delayed gross brain atrophy, and prolonged survival [44]”

    From Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers (2019) · cites this paper as [44]

    The Results section on the rTg4510 tauopathy model reports rescued object-recognition memory, reduced CA1 neuronal loss, and less hippocampal atrophy with trazodone. It does not establish that gross brain atrophy was delayed over time. Crucially, the same section says survival studies in these mice were not possible; the reported lifespan increase was in prion-infected mice, not the tauopathy model. (LLM, conf=0.90)

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Metadata

Authors
Halliday, M., Radford, H., Zents, K. A. M., Molloy, C., Moreno, J. A., Verity, N. C., Smith, E., Ortori, C. A., Barrett, D. A., Bushell, M., & Mallucci, G. R.
Affiliations
  • MRC Toxicology Unit (GB)
  • University of Cambridge (GB)
  • 1 MRC Toxicology Unit, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK
  • University of Nottingham (GB)
Corresponding author
Mallucci, Giovanna R.
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2017-04-19
Volume
140
Issue
6
Pages
1768-1783
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awx074
PMC
PMC5445255
OpenAlex
W2605803966
Cited by
293
References
5
Citations by year
2026: 16 · 2025: 24 · 2024: 22 · 2023: 26 · 2022: 34 · 2021: 39 · 2020: 36 · 2019: 39 · 2018: 33 · 2017: 22
FWCI
13.66
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Brain (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Repository@Nottingham (University of Nottingham) (publishedVersion, cc-by)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc)
  • Apollo
Funders
  • Medical Research Council, UK
  • Alzheimer’s Society & Alzheimer’s Drug Discovery Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
eIF2α phosphorylation, unfolded protein response, protein synthesis inhibition, drug repurposing, trazodone, dibenzoylmethane, neuroprotection, neurodegeneration, prion disease, tauopathy, frontotemporal dementia, Alzheimer's disease, memory impairment, disease-modifying therapy, phenotypic screening
MeSH terms
Animals, Behavior, Animal, Disease Models, Animal, Memory Disorders, Trazodone, Signal Transduction, Prion Diseases, Neuroprotective Agents, eIF-2 Kinase, Chalcones, Protein Kinase Inhibitors, Mice, Unfolded Protein Response, Frontotemporal Dementia

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