Inorganic nitrate attenuates neuroinflammation after traumatic brain injury via Sialin

Background: Traumatic brain injury (TBI) is a significant concern in neurosurgery due to its severe consequences. Neuroinflammation is a critical response following the initial brain insult, leading to cumulative neuronal damage and chronic neurodegeneration, with limited effective treatments available. Inorganic nitrate, an essential nutrient known for its anti-inflammatory properties, is widely utilized in disease prevention and treatment. This study investigated the short-term effects of inorganic nitrate on neuroinflammation and explored the role of Sialin in neuroprotection during the early phase post-TBI. Methods: Male C57BL/6 mice underwent TBI using an electrically controlled cortical impactor (eCCI) model. Animals were administered nitrate or sterile saline intragastrically twice daily for 1,3 or 7 days post-injury (dpi) until sacrifice. Neurobehavioral function was evaluated, and brain tissues were collected for morphological, histopathological, and molecular analyses. Results: Nitrate enhanced neurobehavioral function recovery and improved neurological outcomes at 3 dpi. While nitrate did not significantly reduce structural damage, it did decrease neuronal loss and apoptosis in the early stages of TBI. RNA-seq of injured brains at 3 dpi revealed more genes and signaling pathways linked to immune processes following early nitrate treatment compared to the vehicle, indicating inflammation inhibition. This was further confirmed at the mRNA and protein levels. Specifically, key gene markers of inflammatory mediators were notably suppressed by early nitrate compared to the corresponding TBI vehicle groups. However, the knockdown of Slc17a5 reduced the effectiveness of nitrate on short-term neurobehavior in TBI mice and nullified its anti-inflammatory effects. Conclusion: Inorganic nitrate can improve neurological outcomes and attenuate neuroinflammation following TBI, attributed in part to the normalisation of the inflammatory response mediated by Sialin. The discovery lays a promising groundwork for the protective effects of nitrate in TBI conditions.