Attenuation of doxorubicin-induced cardiotoxicity by mdivi-1: a mitochondrial division/mitophagy inhibitor

Doxorubicin is one of the most effective anti-cancer agents. However, its use is associated with adverse cardiac effects, including cardiomyopathy and progressive heart failure. Given the multiple beneficial effects of the mitochondrial division inhibitor (mdivi-1) in a variety of pathological conditions including heart failure and ischaemia and reperfusion injury, we investigated the effects of mdivi-1 on doxorubicin-induced cardiac dysfunction in naïve and stressed conditions using Langendorff perfused heart models and a model of oxidative stress was used to assess the effects of drug treatments on the mitochondrial depolarisation and hypercontracture of cardiac myocytes. Western blot analysis was used to measure the levels of p-Akt and p-Erk 1/2 and flow cytometry analysis was used to measure the levels p-Drp1 and p-p53 upon drug treatment. The HL60 leukaemia cell line was used to evaluate the effects of pharmacological inhibition of mitochondrial division on the cytotoxicity of doxorubicin in a cancer cell line. Doxorubicin caused a significant impairment of cardiac function and increased the infarct size to risk ratio in both naïve conditions and during ischaemia/reperfusion injury. Interestingly, co-treatment of doxorubicin with mdivi-1 attenuated these detrimental effects of doxorubicin. Doxorubicin also caused a reduction in the time taken to depolarisation and hypercontracture of cardiac myocytes, which were reversed with mdivi-1. Finally, doxorubicin caused a significant elevation in the levels of signalling proteins p-Akt, p-Erk 1/2, p-Drp1 and p-p53. Co-incubation of mdivi-1 with doxorubicin did not reduce the cytotoxicity of doxorubicin against HL-60 cells. These data suggest that the inhibition of mitochondrial fission protects the heart against doxorubicin-induced cardiac injury and identify mitochondrial fission as a new therapeutic target in ameliorating doxorubicin-induced cardiotoxicity without affecting its anti-cancer properties

Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebral-administered homocysteine in mice

High levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy) are associated with neurovascular diseases. H(2)S, a metabolite of Hcy, has a potent anti-oxidant and anti-inflammatory activity; however, the effect of H(2)S has not been explored in Hcy (IC) induced neurodegeneration and neurovascular dysfunction in mice. Therefore, the present study was designed to explore the neuroprotective role of H(2)S on Hcy induced neurodegeneration and neurovascular dysfunction. To test this hypothesis we employed wild type (WT) males ages 8–10 weeks, WT+ artificial cerebrospinal fluid (aCSF), WT+ Hcy (0.5μmol/μl) intracerebral injection (I.C., one time only prior to NaHS treatment), WT+Hcy +NaHS (sodium hydrogen sulfide, precursor of H(2)S, 30 μmol/kg, body weight). NaHS was injected intra-peritoneally (I.P.) once daily for the period of 7 days after the Hcy (IC) injection. Hcy treatment significantly increased MDA, nitrite level, acetylcholinestrase activity, TNFα, IL1β, GFAP, iNOS, eNOS and decreased glutathione level indicating oxidative-nitrosative stress and neuroinflammation as compared to control and aCSF treated groups. Further, increased expression of NSE, S100B and decreased expression of (PSD95, SAP97) synaptic protein indicated neurodegeneration. Brain sections of Hcy treated mice showed damage in the cortical area and periventricular cells. TUNEL positive cells and Fluro Jade-C staining indicated apoptosis and neurodegeneration. The increased expression of MMP9, MMP2 and decreased expression of TIMP-1, TIMP-2, tight junction proteins (ZO1, Occuldin) in Hcy treated group indicate neurovascular remodeling. Interestingly, NaHS treatment significantly attenuated Hcy induced oxidative stress, memory deficit, neurodegeneration, neuroinflammation and cerebrovascular remodeling. The results indicate that H(2)S is effective in providing protection against neurodegeneration and neurovascular dysfunction