Mdivi-1 ameliorates early brain injury after subarachnoid hemorrhage via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.

Aberrant modulation of mitochondrial dynamic network, which shifts the balance of fusion and fission towards fission, is involved in brain damage of various neurodegenerative diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. A recent research has shown that the inhibition of mitochondrial fission alleviates early brain injury after experimental subarachnoid hemorrhage, however, the underlying molecular mechanisms have remained to be elucidated. This study was undertaken to characterize the effects of the inhibition of dynamin-related protein-1 (Drp1, a dominator of mitochondrial fission) on blood-brain barrier (BBB) disruption and neuronal apoptosis following SAH and the potential mechanisms. The endovascular perforation model of SAH was performed in adult male Sprague Dawley rats. The results indicated Mdivi-1(a selective Drp1 inhibitor) reversed the morphologic changes of mitochondria and Drp1 translocation, reduced ROS levels, ameliorated the BBB disruption and brain edema remarkably, decreased the expression of MMP-9 and prevented degradation of tight junction proteins-occludin, claudin-5 and ZO-1. Mdivi-1 administration also inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB), leading to decreased expressions of TNF-ɑ, IL-6 and IL-1ß. Moreover, Mdivi-1 treatment attenuated neuronal cell death and improved neurological outcome. To investigate the underlying mechanisms further, we determined that Mdivi-1 reduced p-PERK, p-eIF2α, CHOP, cleaved caspase-3 and Bax expression as well as increased Bcl-2 expression. Rotenone (a selective inhibitor of mitochondrial complexes I) abolished both the anti-BBB disruption and anti-apoptosis effects of Mdivi-1. In conclusion, these data implied that excessive mitochondrial fission might inhibit mitochondrial complex I to become a cause of oxidative stress in SAH, and the inhibition of Drp1 by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.

Fan LF ，He PY ，Peng YC ，Du QH ，Ma YJ ，Jin JX ，Xu HZ ，Li JR ，Wang ZJ ，Cao SL ，Li T ，Yan F ，Gu C ，Wang L ，Chen G ... -  《-》

Mdivi-1 Alleviates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats, Possibly via Inhibition of Drp1-Activated Mitochondrial Fission and Oxidative Stress.

Wu P ，Li Y ，Zhu S ，Wang C ，Dai J ，Zhang G ，Zheng B ，Xu S ，Wang L ，Zhang T ，Zhou P ，Zhang JH ，Shi H ... -  《-》

Mdivi-1 alleviates blood-brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation.

Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. Our previous studies proved that the inhibition of Drp1 may help attenuate traumatic brain injury (TBI)-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis. However, the molecular mechanisms of Drp1 after TBI remain poorly understood. In this study, we investigated the role of mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibitor of Drp1, in underlying mechanisms of general autophagy and mitochondria autophagy (mitophagy) after experimental TBI. In vivo, we found that autophagosomes accumulated in cortical neurons at 24h after TBI, owing to the enhanced autophagy indicated by the accumulation of LC3 and the decrease of p62; but Mdivi-1 reversed the enhancement. Mdivi-1 also alleviated the number of LC3 puncta and TUNEL-positive structures in cells, indicating that autophagy maybe involved in Mdivi-1's anti-apoptosis effects. Then, the expression level of mitochondrial dynamics related and mitophagy related proteins was assessed using the isolated mitochondria. The results showed that TBI-induced mitochondrial fission (represented by Drp1), mtDNA concentration down-regulation and PTEN induced putative kinase 1 (PINK1)-Parkin mediated mitophagy activation were all inhibited by Mdivi-1. In addition, TBI-induced blood-brain barrier (BBB) disruption and matrix metalloproteinases (MMP)-9 expression up-regulation were inhibited following Mdivi-1 treatment. In vitro, Mdivi-1 significantly alleviated the scratch injury-induced cell death, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production and ATP reduction in primary cortical neurons (PCNs). Additionally, the lysosome inhibitor chloroquine (CQ) abrogated the Mdivi-1-induced decrease in autophagosomes accumulation and cell death at 24h both in the basal state and under the conditions of scratch cell injury. Together, these data demonstrate that Mdivi-1 mitigates TBI-induced BBB disruption and cell death at least in part by a mechanism involving inhibiting autophagy dysfunction and mitophagy activation.

Wu Q ，Gao C ，Wang H ，Zhang X ，Li Q ，Gu Z ，Shi X ，Cui Y ，Wang T ，Chen X ，Wang X ，Luo C ，Tao L ... -  《-》

PARP inhibition attenuates early brain injury through NF-κB/MMP-9 pathway in a rat model of subarachnoid hemorrhage.

Poly (ADP-ribose) polymerases (PARPs) play an important role in a range of neurological disorders, however, the role of PARP in early brain injury after subarachnoid hemorrhage (SAH) remains unclear. This study was designed to explore the role and the potential mechanisms of PARP in early brain injury after SAH. Eighty-nine male SD rats were randomly divided into the Sham group, SAH+Vehicle group and SAH+PARP inhibitor (PJ34) group. An endovascular perforation model was used to induce SAH in rats. PJ34 (10mg/kg) or vehicle (0.9% NaCl) was intraperitoneally administered at 5min and 8h after SAH induction. Mortality, SAH grades, neurological function, evans blue extravasation, brain edema, immunofluorescence staining and western blotting were performed. PJ34 reduced BBB permeability and brain edema, improved neurological function and attenuated neuronal cell death in the rat model of SAH. Moreover, PJ34 inhibited the nuclear translocation of NF-κB, decreased the expression of the proinflammatory cytokines IL-1ß, IL-6 and TNF-α, reduced the expression of MMP-9, prevented the degradation of tight junction proteins, and decreased microglia activation. These data indicated that PARP inhibition through PJ34 might be an important therapeutic drug for SAH.

Chen T ，Wang W ，Li JR ，Xu HZ ，Peng YC ，Fan LF ，Yan F ，Gu C ，Wang L ，Chen G ... -  《-》

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome.

Shao A ，Wu H ，Hong Y ，Tu S ，Sun X ，Wu Q ，Zhao Q ，Zhang J ，Sheng J ... -  《-》