Proteomic Profiling Reveals Region-Specific Neuroimmune and Apoptotic Signatures Induced by Bothrops jararaca Venom Toxins in the Murine Brain

Human envenomation by Bothrops species can lead to systemic effects such as cardiovascular disturbances, coagulopathy, renal failure, and central nervous system (CNS) complications, including hemorrhagic and ischemic strokes. Although Bothrops jararaca is a medically significant species implicated in cases of human stroke, the CNS-specific effects of its venom remain poorly understood. In this study, we employed label-free mass spectrometry-based proteomics to characterize venom-induced alterations in the cerebral cortex and brainstem of mice following intramuscular injection of B. jararaca venom, and to assess the protective effects of Bothrops antivenom. Distinct proteomic changes were identified in both brain regions. Functional enrichment and protein-protein interaction analyses revealed activation of immune-related and pro-apoptotic pathways, including MAPK/JNK signaling in the brainstem and endothelial injury/inflammatory signaling in the cortex. Antivenom treatment partially reversed venom-induced protein abundance changes in a tissue- and time-dependent manner. Together, our findings reveal region-specific molecular responses to B. jararaca envenomation in the CNS. Importantly, we demonstrate for the first time that venom-induced endothelial injury and inflammation may underlie cerebrovascular and CNS pathologies. These results support the hypothesis that B. jararaca venom contributes to CNS complications by promoting vascular disruption and neuroinflammation, potentially explaining the stroke-like outcomes observed in clinical cases of bothropic envenomation.