AUTHOR=Refat M. Selim Heba Mohammed , El-Gazar Amira A. , Abdallah Dalaal M. , Abo-Zalam Hagar B. , Ragab Ghada M. , Abdallah Ahmed N. , El-Gazar Rabab A. , Alshehri Sultan , Yousef Einas M. , Ballal Rayan , Aljarallah Sahar N. , Saleh Asmaa , Abou Chahin Nada F. , Alsammak Naheda S. , Mandil Rasha A. , El-Abhar Hanan S. 

TITLE=Parthanatos drives cognitive decline in repeated brain trauma: MSC-derived exosomes as a novel therapeutic strategy

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1622018

DOI=10.3389/fphar.2025.1622018

ISSN=1663-9812

ABSTRACT=IntroductionRepetitive traumatic brain injury (RTBI) represents a cumulative neurological insult associated with progressive neurodegeneration and limited therapeutic options. In this study, we uniquely evaluate the neuroprotective potential of mesenchymal stem cell (MSC)-derived exosomes in a rat model of RTBI, an area scarcely explored.MethodsRTBI was induced via a controlled mechanical impact to the skull once every day for 5 days. MSC-derived exosomes were administered 24 h after the final insult in two paradigms: a single dose (MSC-Ex1) with 2 weeks of follow-up, and a dual dose (MSC-Ex2) given 1 week apart, with sacrifice 1 week later. Rats were assigned to four groups: control, RTBI, RTBI + MSC-Ex1, and RTBI + MSC-Ex2.ResultsMSC-derived exosome regimens comparably restored cognitive performance in the Novel Object Recognition and Y-maze tests. While both treatment paradigms preserved cortical histoarchitecture, the double-dose regimen led to a more pronounced restoration compared to the moderate tissue recovery observed in the single-dose group. Crucially, this work identifies parthanatos inhibition as a novel mechanistic axis for MSC-derived exosomes-mediated neuroprotection. MSC-derived exosomes attenuated excitotoxicity and oxidative stress, quelling the parthanatos cascade by suppressing PARP1, PAR polymers, nuclear AIF and MIF, as well as calpain, key executors of this caspase-independent cell death pathway. Additionally, MSC-derived exosomes normalized cyclophilin B and Hsp70 levels, suggesting their compensatory role in modulating the endogenous stress response.ConclusionOverall, these findings demonstrate that MSC-derived exosomes counteract RTBI-induced neurodegeneration through multifaceted mechanisms, with parthanatos suppression at the core. Importantly, the dual-dosing regimen conferred no significant benefit over the single dose, highlighting the therapeutic promise of early intervention. This study positions MSC-derived exosomes as a novel, cell-free therapy capable of intercepting RTBI-induced neuropathology by targeting an under recognized form of programmed cell death.