European journal of pharmacology · 2026
Dimethyl fumarate attenuates post-infarct myocardial injury and is associated with modulation of the NRG-1/ErbB2/Akt pathway and reduction of oxidative stress.
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Tekin Işık, Gundogdu Gulsah, Kilic-Erkek Ozgen, Anber Tunahan, Abban-Mete Gulcin
Аннотация
BACKGROUND: Dimethyl fumarate (DMF) is a clinically approved antioxidant and anti-inflammatory agent. This study investigated whether DMF treatment is associated with enhanced myocardial repair after isoproterenol (ISO)-induced myocardial infarction (MI) with a focus on the neuregulin-1 (NRG-1)/ErbB2/protein kinase B (Akt) pathway.
METHODS: MI was induced in male Sprague-Dawley rats via subcutaneous ISO administration (85 mg/kg, two doses 24 h apart). Rats were assigned to Control, MI, Tween-80, and DMF groups. DMF (25 mg/kg/day, oral) was administered for 21 days, and rats were sacrificed on days 7 and 21 to evaluate early and subacute responses. Serum cardiac injury markers, oxidative stress parameters [total antioxidant-oxidant status (TAS-TOS), and oxidative stress index (OSI)], and cardiac tissue levels of NRG-1, ErbB2, PI3K, and Akt-1 were measured. Histological and immunohistochemical analyses assessed myocardial structure, fibrosis, apoptosis (TUNEL), proliferation (BrdU), and progenitor cell activation (c-Kit).
RESULTS: DMF significantly reduced serum troponin-I, creatine kinase-MB, and lactate dehydrogenase levels in the early phase. It improved oxidative balance by increasing TAS and reducing TOS and OSI, while increasing myocardial NRG-1, ErbB2, and Akt-1 levels compared to the MI group. Histological analyses showed preserved fiber integrity, reduced fibrosis, and fewer apoptotic nuclei. Increased BrdU- and c-Kit-positive cells indicated enhanced cardiomyocyte proliferation and progenitor cell activation through the subacute phase.
CONCLUSION: DMF attenuated myocardial injury and was associated with modulation of the NRG-1/ErbB2/Akt signaling pathway, improved redox balance, and enhanced indices of cellular repair across early and subacute post-infarction periods. These findings suggest that DMF may represent a promising candidate for pharmacological repurposing in post-infarction recovery; however, further mechanistic studies are required to confirm causality.
METHODS: MI was induced in male Sprague-Dawley rats via subcutaneous ISO administration (85 mg/kg, two doses 24 h apart). Rats were assigned to Control, MI, Tween-80, and DMF groups. DMF (25 mg/kg/day, oral) was administered for 21 days, and rats were sacrificed on days 7 and 21 to evaluate early and subacute responses. Serum cardiac injury markers, oxidative stress parameters [total antioxidant-oxidant status (TAS-TOS), and oxidative stress index (OSI)], and cardiac tissue levels of NRG-1, ErbB2, PI3K, and Akt-1 were measured. Histological and immunohistochemical analyses assessed myocardial structure, fibrosis, apoptosis (TUNEL), proliferation (BrdU), and progenitor cell activation (c-Kit).
RESULTS: DMF significantly reduced serum troponin-I, creatine kinase-MB, and lactate dehydrogenase levels in the early phase. It improved oxidative balance by increasing TAS and reducing TOS and OSI, while increasing myocardial NRG-1, ErbB2, and Akt-1 levels compared to the MI group. Histological analyses showed preserved fiber integrity, reduced fibrosis, and fewer apoptotic nuclei. Increased BrdU- and c-Kit-positive cells indicated enhanced cardiomyocyte proliferation and progenitor cell activation through the subacute phase.
CONCLUSION: DMF attenuated myocardial injury and was associated with modulation of the NRG-1/ErbB2/Akt signaling pathway, improved redox balance, and enhanced indices of cellular repair across early and subacute post-infarction periods. These findings suggest that DMF may represent a promising candidate for pharmacological repurposing in post-infarction recovery; however, further mechanistic studies are required to confirm causality.