3-(2-4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3h)-quinazolinone and Infarction--Middle-Cerebral-Artery

Disturbance of the balance between mitochondrial fission and fusion has been implicated in cerebral ischemia and several neurodegenerative diseases, whereas the underlying mechanisms remain poorly understood. In the present study, we attempted to investigate the role of dynamin-related protein 1 (Drp1), a key mitochondrial fission protein, in the pathogenesis of cerebral ischemia.. Using Drp1 siRNA or Mdivi-1, a small molecule inhibitor of Drp1, we examined the effect of Drp1 knockdown or inhibition on oxygen-glucose deprivation (OGD)-induced mitochondrial dysfunction and death of SH-SY-5Y cells. Cell death and viability were evaluated with LDH and MTT assays, respectively, and mitochondrial morphology, mitochondrial membrane potential (Δψm), and ATP production were assessed using epifluorescence microscopy, flow cytometry, and HPLC, respectively. Moreover, to examine the effect of Drp1 inhibition on ischemic brain injury, middle cerebral artery occlusion (MCAO) mice were injected (i.p.) with Mdivi1, and blood-brain barrier permeability, brain water content, and cell apoptosis were assessed.. Knockdown or inhibition of Drp1 by Mdivi-1 significantly attenuated OGD-induced cell death in SH-SY-5Y cells, associated with reduced morphological change of mitochondria and attenuated Bax insertion,oligomerization. Moreover, treatment of the MCAO mice with Mdivi-1 remarkably reduced the infarct volume and neurological deficits in a dose-dependent manner, associated with marked reduction of mitochondrial fragmentation and BAX expression.. Down-regulation or inhibition of Drp1 may reduce cerebral ischemic damage through maintaining normal mitochondrial morphology and function, and decreasing Bax insertion and oligomerization in mitochondria.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Blood-Brain Barrier; Brain Edema; Capillary Permeability; Cell Hypoxia; Cell Line, Tumor; Disease Models, Animal; Gene Expression Regulation; Glucose; Humans; Infarction, Middle Cerebral Artery; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Neuroblastoma; Quinazolinones

Mitochondrial division inhibitor (mdivi-1) is a derivative of quinazolinone that acts as a selective inhibitor of a mitochondrial fission protein Drp1. A previous study demonstrated that as a selective inhibitor of Drp1, mdivi-1 has a protective effect in an experimental model of heart ischemia/reperfusion injury. In this study, we investigated the protective effects of mdivi-1 on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that mdivi-1 (1.2mg/kg) significantly reduced cerebral damage induced by ischemia/reperfusion. This neuroprotective effect was dose-dependent. Mdivi-1 treatment blocked apoptotic cell death in cerebral ischemia/reperfusion injury, and significantly decreased the expression of Drp1 and Cytochrome C. These results suggest that mdivi-1 exerts neuroprotective effects against nerve injury after cerebral ischemia/reperfusion, and the underlying mechanism may be through the prevention of Cytochrome C release and suppression of the mitochondrial apoptosis pathway.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Cytochromes c; Dynamins; Infarction, Middle Cerebral Artery; Male; Neurons; Neuroprotective Agents; Quinazolinones; Rats; Rats, Wistar; Reperfusion Injury; RNA, Messenger