P7C3-A20 prevents whole brain radiotherapy-induced chronic hippocampal redox imbalance and neuropsychiatric impairment in mice

Edwin Vázquez-Rosa; Min-Kyoo Shin; Kalyani Chaubey; Sarah Barker; Sofia G Corella; Suwarna Chakraborty; Sunil Jamuna Tripathi; Youngmin Yu; Jiwon Hyung; Himanshu Dashora; Jing Hao; Coral J Cintrón-Pérez; Zea Bud; Matasha Dhar; Emiko Miller; Yeojung Koh; Kate P Lindley; Vidya Indrakumar; Rocio Aguila Rodriguez; Kranti A Mapuskar; Joshua D Schoenfeld; Hisashi Fujioka; Luke I Szweda; Brigid M Wilson; Jennifer S Yu; Bindu D Paul; Douglas R Spitz; Bryan G Allen; Andrew A Pieper

doi:10.1016/j.redox.2026.104052

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P7C3-A20 prevents whole brain radiotherapy-induced chronic hippocampal redox imbalance and neuropsychiatric impairment in mice

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P7C3-A20 prevents whole brain radiotherapy-induced chronic hippocampal redox imbalance and neuropsychiatric impairment in mice

Edwin Vázquez-Rosa, Min-Kyoo Shin, Kalyani Chaubey, Sarah Barker, Sofia G Corella, Suwarna Chakraborty, Sunil Jamuna Tripathi, Youngmin Yu, Jiwon Hyung, Himanshu Dashora, …

Redox biology, Vol.91, 104052

04/2026

DOI: 10.1016/j.redox.2026.104052

PMID: 41680036

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Abstract

Whole brain radiotherapy (WBRT) prolongs survival for patients with brain metastases but produces persistent oxidative injury to the brain and long-term neuropsychiatric sequelae, for which no approved neuroprotective therapies exist. Here, we show that a single course of WBRT produces chronic oxidative stress in mice that persists for at least one year, equivalent to decades in humans, and selectively injures the hippocampus, causing cognitive decline and depressive-like behavior. Daily administration of P7C3-A20, a neuroprotective compound that stabilizes brain nicotinamide adenine dinucleotide (NAD ) homeostasis, markedly reduced oxidative stress and prevented hippocampal pathology for one year after WBRT. P7C3-A20 treatment suppressed neuroinflammation, axonal injury, loss of hippocampal neural precursor cells, blood-brain barrier breakdown, and microglial lipid droplet accumulation, resulting in long-term preservation of cognition and brain health. Crucially, P7C3-A20 did not impair the antitumor efficacy of radiation. These findings identify NAD homeostasis stabilization as a promising strategy to mitigate radiation-induced oxidative damage and to prevent long-term neuropsychiatric complications of WBRT.

Oxidative Stress

Neuroprotection

P7C3-A20

Neurodegeneration

Depression

Hippocampus

Whole brain irradiation

Details

Title: Subtitle: P7C3-A20 prevents whole brain radiotherapy-induced chronic hippocampal redox imbalance and neuropsychiatric impairment in mice
Creators: Edwin Vázquez-Rosa - University Hospitals of Cleveland
Min-Kyoo Shin - University Hospitals of Cleveland
Kalyani Chaubey - Case Western Reserve University
Sarah Barker - Case Western Reserve University
Sofia G Corella - Case Western Reserve University
Suwarna Chakraborty - Johns Hopkins Medicine
Sunil Jamuna Tripathi - Johns Hopkins Medicine
Youngmin Yu - Case Western Reserve University
Jiwon Hyung - University Hospitals of Cleveland
Himanshu Dashora - Cleveland Clinic Lerner College of Medicine
Jing Hao - Cleveland Clinic Lerner College of Medicine
Coral J Cintrón-Pérez - University Hospitals of Cleveland
Zea Bud - Case Western Reserve University
Matasha Dhar - Case Western Reserve University
Emiko Miller - University Hospitals of Cleveland
Yeojung Koh - Case Western Reserve University
Kate P Lindley - Case Western Reserve University
Vidya Indrakumar - University Hospitals of Cleveland
Rocio Aguila Rodriguez - University Hospitals of Cleveland
Kranti A Mapuskar - University of Iowa
Joshua D Schoenfeld - Dana-Farber Brigham Cancer Center
Hisashi Fujioka - Case Western Reserve University
Luke I Szweda - University of Arizona
Brigid M Wilson - Louis Stokes Cleveland VA Medical Center
Jennifer S Yu - Cleveland Clinic
Bindu D Paul - Johns Hopkins University
Douglas R Spitz - University of Iowa
Bryan G Allen - University of Iowa
Andrew A Pieper - Case Western Reserve University
Resource Type: Journal article
Publication Details: Redox biology, Vol.91, 104052
DOI: 10.1016/j.redox.2026.104052
PMID: 41680036
NLM abbreviation: Redox Biol
ISSN: 2213-2317
eISSN: 2213-2317
Publisher: Elsevier
Grant note: NCI/NIH UIHC-CCOM Iowa Aging Initiative: P01 CA217797 NCI: R25 CA221718 Gateway for Cancer Research: G-17-1500, NCP/NIH PO1 CA244091 NCI/NIH: P30 CA086862 Alzheimer' s Disease Translational Data Science Training Program NIH: T32 AG071474 Case Western Medical Scientist Training program NIH: T32 GM007250 NIH: F31 5F31Ag089912 NIH/NIA: F99 Ag083111 New Faculty Startup Fund: 370C-20220110 Creative-Pioneering Researchers Program: 370C-20230108, 370C-20240120 Seoul National UniversityNational Research Foundation of Korea: RS-2023-00209597, RS-2024-00352229, RS-2024-00440679, RS-2024-00466703, BT240041 BrightFocus Foundation: A2019551F Department of Veterans Affairs of the United States government
This study was funded by the Valour Foundation (AAP), Project 19PABH134580006 AHA/Allen Initiative in Brain Health and Cognitive Impairment (AAP and BDP), T32 CA078586 Free Radical and Radiation Biology, University of Iowa (EV-R), Department of Defense Peer-Reviewed Alzheimer's Research Program (PRARP) Award AZ210092 (W81XWH-22-1-0129) (EV-R), R01NS124081-01A1 (JSY), VeloSano (JSY), Case CCC (JSY), Cleveland Clinic (JSY), NIA RO1AG066707 (AAP), the Rebecca E. Barchas, M.D., DLFAPA Case Western Reserve University Chair in Translational Psychiatry (AAP), Elizabeth Ring Mather & William Gwinn Mather Fund (AAP), S. Livingston Samuel Mather Trust (AAP), G.R. Lincoln Family Foundation (AAP), Wick Foundation (AAP), Leonard Krieger Fund of the Cleveland Foundation (AAP), NIA/NIH R01AG071512 (BDP and AAP), JHU Catalyst Award (BDP), Louis Stokes VA Medical Center resources and facilities (AAP), NCI/NIH UIHC-CCOM Iowa Aging Initiative P01 CA217797 (BGA and DRS), NCI R25 CA221718 (AAP, KPL), Gateway for Cancer Research G-17-1500 (BGA), DRS was additionally supported by NCP/NIH PO1 CA244091 (DRS), and NCI/NIH P30 CA086862 (BGA, DRS, AAP). SB and EM were supported by the Alzheimer' s Disease Translational Data Science Training Program NIH T32 AG071474. SB was also supported by Case Western Medical Scientist Training program NIH T32 GM007250. EM was also supported by NIH F31 5F31Ag089912. YK was supported by NIH/NIA F99 Ag083111. M-KS was supported by the New Faculty Startup Fund (370C-20220110), Creative-Pioneering Researchers Program (370C-20230108), and a research grant (370C-20240120) from Seoul National University. M-KS also acknowledges support from the National Research Foundation of Korea (RS-2023-00209597, RS-2024-00352229, RS-2024-00440679, RS-2024-00466703), Seoul R&BD program (BT240041) and donors of Alzheimer's Disease Research, a program of Bright Focus Foundation (A2019551F). Views expressed are those of the authors and do not reflect the position or policy of the Department of Veterans Affairs of the United States government.r NCI/NIH UIHC-CCOM Iowa Aging Initiative P01 CA217797 (BGA and DRS) , NCI R25 CA221718 (AAP, KPL) , Gateway for Cancer Research G-17-1500 (BGA) , DRS was additionally supported by NCP/NIH PO1 CA244091 (DRS) , and NCI/NIH P30 CA086862 (BGA, DRS, AAP) . SB and EM were supported by the Alzheimer' s Disease Translational Data Science Training Program NIH T32 AG071474. SB was also supported by Case Western Medical Scientist Training program NIH T32 GM007250. EM was also supported by NIH F31 5F31Ag089912. YK was supported by NIH/NIA F99 Ag083111. M-KS was supported by the New Faculty Startup Fund (370C-20220110) , Creative-Pioneering Researchers Program (370C-20230108) , and a research grant (370C-20240120) from Seoul National University. M-KS also acknowledges support from the National Research Foundation of Korea (RS-2023-00209597, RS-2024-00352229, RS-2024-00440679, RS-2024-00466703) , Seoul R&BD program (BT240041) and donors of Alzheimer's Disease Research, a program of BrightFocus Foundation (A2019551F) . Views expressed are those of the authors and do not reflect the position or policy of the Department of Veterans Affairs of the United States government.
Language: English
Electronic publication date: 02/11/2026
Date published: 04/2026
Academic Unit: Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9985139492802771

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