Neuroprotective effects of Saxagliptin in traumatic brain injury: ameliorating oxidative stress, neuroinflammation, and apoptosis.

Traumatic Brain Injury (TBI) is a significant global health issue characterized by disruptions in normal brain function due to external mechanical forces. Saxagliptin, a Dipeptidyl Peptidase-4 (DPP-4) inhibitor primarily used for diabetes management, has demonstrated potential anti-inflammatory effects that may offer therapeutic benefits for Central Nervous System (CNS) disorders. Using a network pharmacology approach, we identified Saxagliptin's molecular targets relevant to TBI pathology. Male Sprague Dawley rats were subjected to TBI via a weight-drop method and were randomly assigned to one of four groups (n = 10 per group): sham, TBI + vehicle, TBI + Saxagliptin (1 mg/kg/day), and TBI + Saxagliptin (3 mg/kg/day). Neuroprotective effects were assessed through neurobehavioral tests, brain water content measurement, biochemical assays for oxidative stress and inflammatory markers, and histopathological analysis of brain tissue. Network pharmacology identified 49 intersecting targets between Saxagliptin and TBI, with key roles in apoptosis and neuroinflammation pathways. In vivo results revealed that saxagliptin treatment markedly improved neurobehavioral outcomes. Histological analysis showed a decrease in neuronal cell death following Saxagliptin treatment. Biochemical assessments revealed that Saxagliptin mitigated TBI-induced oxidative stress markers, including oxidative DNA damage. Furthermore, Saxagliptin attenuated neuroinflammation, as shown by reduced levels of iNOS, COX-2, IL-6, and TNF-α, and ameliorated blood-brain barrier (BBB) damage. Additionally, Saxagliptin reduced apoptosis by lowering Bax, Caspase 3 levels and increasing Bcl-2 levels. Saxagliptin exhibits notable neuroprotective effects in TBI by mitigating oxidative stress, reducing neuroinflammation, and preventing neuronal apoptosis. These findings suggest that Saxagliptin could be a viable therapeutic agent for improving outcomes in TBI management.