Timing dictates efficacy: evaluating the prophylactic and therapeutic potential of dimethyl fumarate against LPS-induced shock.

BACKGROUND

Acute kidney injury (AKI) is a serious and often fatal condition that is caused by endotoxemia as a result of systemic inflammation and uncontrolled oxidative stress. Although dimethyl fumarate (DMF) has shown to have immunomodulatory and antioxidant activity, its specific prophylactic and therapeutic activity in endotoxemia-induced AKI remains unclear.

AIM: to study DMF's effect on endotoxemia-induced AKI in a mouse in vivo model.

METHODS

We divided the mice (Swiss albino) into eight equal groups. The endotoxemia-induced AKI was treated by intraperitoneal injection with LPS (5 mg/kg). Prophylactic cohorts received oral DMF (50 or 100 mg/kg/day) for three consecutive days prior to the challenge. Therapeutic cohorts were given a single DMF dose one hour after the treatment. At six hours, gross renal function (BUN, creatinine), cytokine levels, Nrf2/HO-1 activation, oxidative damage biomarkers, inflammasome/apoptotic pathways and acute tubular necrosis (ATN) histopathology were assessed.

RESULTS

LPS challenge resulted in severe renal dysfunction, the onset of a massive cytokine storm and acute tubular destruction. The pre-treatment of DMF prevented the TLR4/NF-κB inflammatory pathway and the overall renal cytoarchitecture was preserved. On the other hand, therapeutic DMF demonstrated a unique anti-inflammatory "ceiling effect" where both low and high doses inhibited NF-κB activation. Therapeutic DMF was more robust in structural and functional rescue, upregulating the Nrf2/HO-1 defense axis, neutralizing reactive oxygen species, and blocking the final inflammasome priming and pyroptotic actions.

CONCLUSION

The timing of intervention fundamentally dictates pharmacological efficacy. Prophylaxis offers strong preventative shielding, whereas high-dose therapeutic DMF successfully mitigates ongoing oxidative storms, providing a compelling and highly translatable rationale for clinical repurposing in critical care nephrology.