(−)-P7C3-S243 Protects a Rat Model of Alzheimer’s Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia
| Autor: | Michael Z. Khan, Andrew A. Pieper, Jaymie R. Voorhees, Latisha McDaniel, Matthew T. Remy, Daniel J. Brat, Noelle S. Williams, Eli El Rassi, Coral J. Cintrón-Pérez, Laura M. Dutca, Terry C. Yin |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Aging Carbazoles Disease Neuroprotection Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine P7C3 Alzheimer Disease medicine Animals Cognitive Dysfunction Biological Psychiatry Neuroinflammation Depression (differential diagnoses) Inflammation Amyloid beta-Peptides Behavior Animal Depression Neurogenesis Neurodegeneration Cognition medicine.disease Rats Inbred F344 Rats Disease Models Animal Neuroprotective Agents 030104 developmental biology chemistry Nerve Degeneration Female Rats Transgenic Psychology Neuroglia Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Biological Psychiatry. 84:488-498 |
| ISSN: | 0006-3223 |
| DOI: | 10.1016/j.biopsych.2017.10.023 |
| Popis: | BACKGROUND: In addition to cognitive deficits, Alzheimer’s disease (AD) is also 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 thus be uniquely applicable to patients with AD, given the co-morbid 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 daily (−)-P7C3-S243 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 offered by P7C3 compounds, may represent a new treatment approach for patients suffering from the combination of cognitive deficits and depression associated with AD. |
| Databáze: | OpenAIRE |
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