THE MITOCHONDRIAL DIVISION INHIBITOR MDIVI-1 PROTECTED ORGAN FUNCTION AND EXTENDED THE TREATMENT WINDOW IN RATS WITH UNCONTROLLED HEMORRHAGIC SHOCK

Aim: This study aimed to elucidate whether the application of the mitochondrial division inhibitor Mdivi-1 can protect organ function and prolong the treatment window for traumatic hemorrhagic shock. Methods: Before definitive hemostasis treatment, Mdivi-1 (0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg) was administered to uncontrolled hemorrhagic shock (UHS) model rats. Lactate Ringer's solution plus hydroxyethyl starch (130/0.4) was used as a control. The effects of Mdivi-1 on blood loss; fluid demand; survival time; vital organ function; myocardial mitochondrial structure; mitochondrial function of the heart, liver, kidney, and intestine; and oxidative stress at 1 h after hypotensive resuscitation (50-60 mm Hg) were investigated. In addition, we investigated the effect of varying doses of Mdivi-1 on the maintenance time of hypotensive resuscitation without definitive hemostasis and the beneficial effect of Mdivi-1 after prolonging the duration of hypotensive resuscitation to 2 h. Results: Compared to conventional resuscitative fluid, Mdivi-1 significantly reduced blood loss and fluid demand, improved important organ functions during hypotensive resuscitation, improved animal survival, and reduced the incidence of early death. Mdivi-1 significantly alleviated oxidative stress injury, reduced mitochondrial damage, and restored myocardial mitochondrial structure and mitochondrial function of the heart, liver, kidney, and intestine. In addition, Mdivi-1 increased the maintenance time of hypotensive resuscitation and improved rat survival after the duration of hypotensive resuscitation was prolonged to 2 h. Conclusion: Mdivi-1 significantly prolonged the treatment window for traumatic hemorrhagic shock to 2 h in UHS model rats. The underlying mechanism may be that Mdivi-1 inhibits excessive mitochondrial fission and oxidative stress and improves the structure and function of mitochondria.