Timing dictates efficacy: evaluating the prophylactic and therapeutic potential of dimethyl fumarate against LPS-induced shock
- 1Department of Pharmacology and Toxicology, College of Pharmacy, Al-Mustafa University , ,
Abstract
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.
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BibTeX
@article{mahmood2026timing,
title = {{Timing dictates efficacy: evaluating the prophylactic and therapeutic potential of dimethyl fumarate against LPS-induced shock}},
author = {Ahmed Mohammed Mahmood},
journal = {Frontiers in pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1966178},
url = {https://europepmc.org/article/PMC/PMC13669161},
note = {CC BY},
}
RIS
TY - JOUR
TI - Timing dictates efficacy: evaluating the prophylactic and therapeutic potential of dimethyl fumarate against LPS-induced shock
AU - Ahmed Mohammed Mahmood
PY - 2026
DA - 2026/10/01
JO - Frontiers in pharmacology
DO - 10.3389/fphar.2026.1966178
UR - https://europepmc.org/article/PMC/PMC13669161
AB - 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.
SN - 1663-9812
ER -