Increased semaphorin, neuropilin, and plexin expression plays a role in recovery after traumatic brain injury.

One of the leading causes of death and disability globally, affecting people of all ages, is traumatic brain injury (TBI). Damage to neural tissues associated with TBI can be classified into two categories: primary damage caused by direct mechanical forces resulting from trauma and secondary damage characterized by long-term neuroinflammation resulting from the molecular response of tissues and cells following primary injury. Although the effects of semaphorin (Sema) molecules on neural repair and regeneration are known, their role in the secondary injury process after TBI remains unclear. Sema proteins bind to their receptors, members of the neuropilin and plexin protein families, to carry out their actions. In this study, after mild TBI (mTBI) was induced, an acute mTBI group (observed for 24 h), a short-term mTBI chronic group, a long-term mTBI chronic group, and a sham group were created. As a result, neuronal damage is increased in acute and chronic mTBI models. Males exhibit increased levels of Sem-3 F, Plexin-A1, Neuropilin-1, and TNF-α protein expression in the hippocampus, particularly following chronic short-term mTBI. In addition, the chronic long-term group presented greater neuropilin 1 gene expression in the hypothalamus, hippocampus, pituitary, and hypophysis. Our findings suggest that semaphorin, neuropilin, and plexin proteins may help create new treatment techniques on the basis of their potential involvement in establishing and recovering from primary and secondary damage following TBI. GRAPHICAL ABSTRACT: Males exhibit increased levels of Sem-3F, Plexin-A1, Neuropilin-1, and TNF-α protein expression in the hippocampus, particularly following chronic short-term mTBI. In addition, the chronic long-term group presented greater neuropilin 1 gene expression in the hypothalamus, hippocampus, pituitary, and hypophysis. Our findings suggest that semaphorin, neuropilin, and plexin proteins may contribute to the development of new treatment techniques based on their potential role in establishing and recovering from primary and secondary damage following traumatic brain injury. [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-026-01788-x.