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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Introduction Repetitive 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. Methods RTBI 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. Results MSC-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

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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