Work

Time-dependent neuroprotective effects of YL-IPA08 in repetitive mild traumatic brain injury associated with changes in Caprin1/SHH signaling

Year: 2026

Type: article

Abstract: Repetitive mild traumatic brain injury (rmTBI) triggers chronic neuroinflammation, oxidative stress, and synaptic dysfunction, resulting in long-term cognitive and emotional impairments. Effective pharmacological interventions remain scarce. Caprin1, a stress-responsive RNA-binding protein, regulates stress granules (SGs) dynamics and mRNA translation, while Sonic Hedgehog (SHH) signaling mediates neurogenesis and glial reactivity. YL-IPA08, a potent translocator protein (TSPO) ligand, exhibits neuroprotective efficacy in several neurological models, yet its temporal effects in rmTBI are unknown. Using a murine thinned-skull rmTBI model, we compared acute (YL-AcT, 0–3 days post-injury) and intermediate-phase (YL-IntT, 8–42 days) YL-IPA08 treatment paradigms. YL-AcT enhanced Caprin1/SHH co-expression, increased Caprin1-associated cytoplasmic granules consistent with SGs-like structures, and elevated DCX + immature neuronal signals in the hippocampal DG without behavioral improvement, suggesting persistent cellular stress responses. In contrast, YL-IntT significantly improved motor, affective, and cognitive performance, reduced Caprin1 and SHH immunoreactivity, decreased the abundance of Caprin1-associated cytoplasmic granules, and partially restored hippocampal cytoarchitecture. YL-IntT also suppressed SHH/C3 co-expression, suggesting attenuation of neurotoxic astrocytic activation. TSPO expression showed dynamic, cell type–specific modulation across astrocytes and other cell populations, supporting a phase-dependent neuroprotective mechanism. Collectively, these findings suggest that YL-IPA08 exerts timing (treatment-window)-dependent neuroprotective effects that are temporally associated with alterations in Caprin1 and SHH signaling proteins, Caprin1-associated stress-responsive granule dynamics, and changes in TSPO expression patterns, potentially contributing to neuron–glia homeostasis under conditions of TSPO modulation. However, the present findings reflect associative relationships, and further studies will be required to determine the causal mechanisms linking TSPO modulation, Caprin1/SHH signaling, and functional recovery following rmTBI.

Source: European Journal of Pharmacology

DOI: 10.1016/j.ejphar.2026.178868