Free radical biology & medicine, 2017-11, Vol.112, p.336-349
2017
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- Autor(en) / Beteiligte
- Titel
- 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
- Ist Teil von
- Free radical biology & medicine, 2017-11, Vol.112, p.336-349
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •SAH could result in mitochondrial morphological changes, Drp1 translocation onto mitochondria and ROS increase.•Mdivi-1 may induce the expression of mitochondrial complex I to reduce SAH-induced oxidative stress.•Mdivi-1 may inhibit oxidative stress-induced NF-κB-dependent BBB disruption to attenuate brain edema in SAH.•Mdivi-1 protects neuron against apoptosis probably through the inhibition of the PERK/ eIF2α/ CHOP pathway.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0891-5849eISSN: 1873-4596DOI: 10.1016/j.freeradbiomed.2017.08.003Titel-ID: cdi_proquest_miscellaneous_1927594854
- Format
- –
- Schlagworte
- Animals, Apoptosis, Apoptosis - drug effects, bcl-2-Associated X Protein - antagonists & inhibitors, bcl-2-Associated X Protein - genetics, bcl-2-Associated X Protein - metabolism, Blood-Brain Barrier - drug effects, Blood-Brain Barrier - metabolism, Blood-brain barrier disruption, Claudin-5 - genetics, Claudin-5 - metabolism, Dynamins - antagonists & inhibitors, Dynamins - genetics, Dynamins - metabolism, Early brain injury, Endoplasmic Reticulum Stress - drug effects, Inflammation, Interleukin-1beta - antagonists & inhibitors, Interleukin-1beta - genetics, Interleukin-1beta - metabolism, Interleukin-6 - antagonists & inhibitors, Interleukin-6 - genetics, Interleukin-6 - metabolism, Male, Matrix Metalloproteinase 9 - genetics, Matrix Metalloproteinase 9 - metabolism, Mdivi-1, Mitochondria - drug effects, Mitochondria - genetics, Mitochondria - metabolism, Mitochondrial Dynamics - drug effects, Mitochondrial Dynamics - genetics, NF-kappa B - antagonists & inhibitors, NF-kappa B - genetics, NF-kappa B - metabolism, Occludin - genetics, Occludin - metabolism, Proto-Oncogene Proteins c-bcl-2 - agonists, Proto-Oncogene Proteins c-bcl-2 - genetics, Proto-Oncogene Proteins c-bcl-2 - metabolism, Quinazolinones - pharmacology, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species - antagonists & inhibitors, Reactive Oxygen Species - metabolism, Subarachnoid hemorrhage, Subarachnoid Hemorrhage - drug therapy, Subarachnoid Hemorrhage - genetics, Subarachnoid Hemorrhage - mortality, Subarachnoid Hemorrhage - pathology, Subarachnoid Space - drug effects, Subarachnoid Space - metabolism, Subarachnoid Space - pathology, Survival Analysis, Tumor Necrosis Factor-alpha - antagonists & inhibitors, Tumor Necrosis Factor-alpha - genetics, Tumor Necrosis Factor-alpha - metabolism, Zonula Occludens-1 Protein - genetics, Zonula Occludens-1 Protein - metabolism