Frontiers in pharmacology · 2026
Timing dictates efficacy: evaluating the prophylactic and therapeutic potential of dimethyl fumarate against LPS-induced shock.
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Mahmood Ahmed Mohammed
Аннотация
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.
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.