Effect of endogenous and exogenous ketosis in acute spinal cord injury in Wistar rats.

Acute spinal cord injury is a condition with a poor prognosis, leading to reduced quality of life and high economic costs for both patients and health systems, and only a minority of patients with this injury can achieve a meaningful recovery. Given the high frequency of traumatic events such as vehicle collisions and falls, research aimed at limiting injury extension, promoting neuronal recovery, and improving prognosis is essential. It has been shown that ketone bodies have anti-inflammatory properties and also mediate the Nrf2 pathway, exerting antioxidant effects. The aim was to identify any alternative to mitigate the extension and progression of secondary injury by using 1,3 butanediol as a {beta}-hydroxybutyrate source. An experimental model (n= 60) of clinically healthy male Wistar rats were used, divided into five groups (n=12) as a control group, while the remaining rats were subjected to extradural spinal cord clipping according to the following groups (n=12): Spinal Cord Injury (SCI); endogenous ketosis + methylprednisolone (Endo-K+MP); exogenous ketosis + methylprednisolone (Exo-K+MP), and methylprednisolone (MP). After 8 hours of spinal cord injury, tissue was collected, immunohistochemistry and PCR analyses were carried out. Nrf2 and 3NT for the antioxidant pathway, and HIF-1, NFkB, NLRP3, TNF-[a] and IL-1{beta} for inflammation were analyzed. Results demonstrated that the groups thrown into a ketosis state had better outcomes, and, according to the Exo-k+MP and Endo-k+MP groups, increased Nrf2 and decreased 3NT (p < 0.05), which resulted in an upregulation of antioxidant pathways. According to HIF-1 and NF{kappa}B, Endo-K+MP showed better outcomes p<0.05 and proinflammatory cytokines showed the same pattern as the standard treatment (MP) p<0.05). Overall, our results also demonstrated a downregulation of inflammatory pathways. Author SummarySpinal cord injury is a devastating condition that frequently results in permanent neurological damage, reduced quality of life, and high social and healthcare costs. Current treatments are limited and mainly focus on reducing inflammation after injury, with methylprednisolone being one of the most commonly used therapies despite its associated adverse effects. Previous studies have shown that ketosis, a metabolic state characterized by increased ketone bodies, has anti-inflammatory and antioxidant properties in several neurological conditions. In this study, we investigated whether inducing ketosis could improve early outcomes after acute spinal cord injury. Using a rat model, we compared the effects of endogenous ketosis (induced by fasting) and exogenous ketosis (induced by ketone precursors), alone or in combination with methylprednisolone. We analyzed inflammatory and oxidative stress pathways using immunohistochemistry and molecular techniques. Our findings show that ketosis enhances the anti-inflammatory and antioxidant effects of methylprednisolone, leading to reduced activation of inflammatory pathways and increased antioxidant responses during the first hours after injury. These results suggest that metabolic interventions such as ketosis may represent a promising complementary strategy to improve early management of spinal cord injury.