Effect of Extracellular Vesicles on Neurobehavioral Sequelae and Late Seizures After Traumatic Brain Injury in a Mouse Model of Controlled Cortical Impact

Abstract

Traumatic brain injury (TBI) is a major global health issue, with approximately 27 million new cases annually. TBI significantly increases the risk of developing post-traumatic epilepsy (PTE), which may emerge weeks to years after the initial injury. Currently, effective therapies for both TBI and PTE remain limited. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have demonstrated anti-inflammatory and neuroprotective effects in preclinical TBI models. VivaZome’s proprietary cells (VZT-PCs) share characteristics with MSCs, including similar surface markers and immunomodulatory properties. Native EVs from VZT-PCs are enriched in microRNAs with known anti-inflammatory properties. This study assessed the therapeutic effect of VZT-PC-derived EVs in a murine model of TBI. Adult C57BL/6 mice underwent controlled cortical impact (CCI) and received either vehicle control or VZT-PC-EVs. Functional recovery was assessed using the Rotarod test and the Elevated Plus maze (EPM) test. After 4 weeks post TBI induction, PTE was evaluated using pentylenetetrazol challenge and video-electroencephalography. Native EV-treated TBI mice showed improved performance in Rotarod trials, where latency to fall was significantly increased at 24 h post injury, indicating enhanced motor coordination. Exploratory behavior in the EPM was also improved following EV administration, indicating mice exhibited reduced anxiety-like behavior. EV-treated mice exhibited a trend toward reduced seizure frequency and increased latency to generalized seizures, though not statistically significant. Collectively, these findings support the therapeutic potential of VZT-PC-derived native EVs in enhancing motor function and possibly reducing epileptogenicity following moderate TBI, highlighting VZT-PCs as a promising source of EVs for brain injury therapy.