Therapeutic effect of neural induced-stem cell-derived exosomes by regulating ERK/p38/NF-κB in traumatic brain injury

Traumatic brain injury (TBI) can occur because of sudden external forces, such as falls or accidents, and it can cause immediate and long-term damage to the central nervous system. In this study, the therapeutic effects of neural-induced human adipose tissue-derived stem cell-derived exosomes (NI-Exo) on TBI were investigated. Exosomes were isolated and characterized through nanoparticle tracking analysis, cryo-transmission electron microscopy, and western blotting analysis. The therapeutic effects of NI-Exo were assessed in LPS-stimulated human microglial cells and TBI mice via behavioral tests (rotarod, elevated body swing, and cylinder tests), qPCR, western blotting analysis, and immunostaining. In the in vitro study, NI-Exo significantly downregulated pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and upregulated anti-inflammatory cytokines (IL-4 and IL-10). In the in vivo study, NI-Exo (1 × 10⁴ or 1 × 10⁵ particles/mL) was administered intracerebroventricularly 1 h post-surgery to verify the effect on the in vivo model. In the TBI mouse model, NI-Exo improved asymmetric behaviors and reduced tissue disruption and cell loss. The protein levels of pro-apoptosis (p53, ROCK1, and Bax) decreased and those of anti-apoptosis (Mcl-1) increased in the NI-Exo group compared with those in the TBI group. Mechanistic investigations revealed that NI-Exo inhibited ERK and p38 phosphorylation, highlighting its role in mitigating neuroinflammation via the ERK/p38/NF-κB signaling pathway. Therefore, NI-Exo promoted anti-inflammation in human microglia and TBI mouse models; it also improved anti-apoptosis in TBI models, thereby offering a promising therapeutic potential for TBI treatment through the ERK/p38/NF-κB pathway.