(−)-P7C3-S243 Protects a Rat Model of Alzheimer’s Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia
Open accessAbstract
BACKGROUND: In addition to cognitive deficits, Alzheimer's disease (AD) is associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments. P7C3 aminopropyl carbazoles promote neuronal survival by enhancing nicotinamide adenine dinucleotide flux in injured neurons. Neuroprotection with P7C3 compounds has been demonstrated in preclinical models of neurodegeneration by virtue of promoting neuronal survival independently of early disease-specific pathology, resulting in protection from cognitive deficits and depressive-like behavior. We hypothesize that P7C3 compounds might be uniquely applicable to patients with AD, given the comorbid presentation of depression and cognitive deficits. METHODS: Aging male and female wild-type and TgF344-AD rats, a well-characterized preclinical AD model, were administered (-)-P7C3-S243 daily for 9 and 18 months, beginning at 6 months of age. Behavioral phenotypes related to cognition and depression were assessed at 15 and 24 months, and brain pathology and biochemistry were assessed at 24 months. RESULTS: (-)-P7C3-S243 safely protected aging male and female wild-type and TgF344-AD rats from cognitive deficits and depressive-like behavior. Depressive-like behavior occurred earlier than cognitive deficits in TgF344-AD rats, consistent with AD in many patients. Treatment with (-)-P7C3-S243 blocked neurodegeneration in TgF344-AD rats, without altering amyloid deposition or indicators of neuroinflammation. CONCLUSIONS: Neuronal cell death-specific treatment approaches, such as P7C3 compounds, may represent a new treatment approach for patients experiencing the combination of cognitive deficits and depression associated with AD.
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P7C3 was shown to be neuroprotective in mouse models of Parkinson disease, Alzheimer disease and ALS.
“P7C3 was shown to be neuroprotective in mouse models of Parkinson disease137, Alzheimer disease157 and ALS158.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [157]
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NAD+ metabolism and its roles in cellular processes during ageing
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- Authors
- Voorhees, J. R., Remy, M. T., Cintrón-Pérez, C. J., El Rassi, E., Khan, M. Z., Dutca, L. M., Yin, T. C., McDaniel, L. N., Williams, N. S., Brat, D. J., & Pieper, A. A.
- Affiliations
- University of Iowa (US)
- The University of Texas Southwestern Medical Center (US)
- Emory University (US)
- Corresponding author
- Pieper, Andrew A.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 84
- Issue
- 7
- Pages
- 488-498
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC6415524
- OpenAlex
- W2767802406
- Cited by
- 78
- References
- 50
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 11 · 2023: 5 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 11
- FWCI
- 6.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (IK2-RX002003, I01 BX002444)
- National Institute of Environmental Health Sciences (P30ES005605)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, NAD+, neuroprotection, neurodegeneration, cognitive impairment, depression-like behavior, neuropsychiatric symptoms, TgF344-AD rats, amyloid deposition, neuroinflammation, neuronal survival
- MeSH terms
- Aging, Alzheimer Disease, Animals, Behavior, Animal, Carbazoles, Depression, Disease Models, Animal, Female, Inflammation, Male, Nerve Degeneration, Neuroglia, Rats, Inbred F344, Amyloid beta-Peptides, Neuroprotective Agents, Rats, Rats, Transgenic, Cognitive Dysfunction
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