scholarly journals SIRT3 Expression Decreases with Reactive Oxygen Species Generation in Rat Cortical Neurons during Early Brain Injury Induced by Experimental Subarachnoid Hemorrhage

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Huang ◽  
Yong Huang ◽  
Ren-qiang Huang ◽  
Cheng-guang Huang ◽  
Wen-hao Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cerebral Cortex ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Cortical Neurons ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Early Brain Injury ◽  
Oxygen Species ◽  
Sirt3 Expression

Sirtuin3 (SIRT3) is an important protein deacetylase which predominantly presents in mitochondria and exhibits broad bioactivities including regulating energy metabolism and counteracting inflammatory effect. Since inflammatory cascade was proved to be critical for pathological damage following subarachnoid hemorrhage (SAH), we investigated the overall expression and cell-specific distribution of SIRT3 in the cerebral cortex of Sprague-Dawley rats with experimental SAH induced by internal carotid perforation. Results suggested that SIRT3 was expressed abundantly in neurons and endothelia but rarely in gliocytes in normal cerebral cortex. After experimental SAH, mRNA and protein expressions of SIRT3 decreased significantly as early as 8 hours and dropped to the minimum value at 24 h after SAH. By contrast, SOD2 expression increased slowly as early as 12 hours after experimental SAH, rose up sharply at the following 12 hours, and then was maintained at a higher level. In conclusion, attenuated SIRT3 expression in cortical neurons was associated closely with enhanced reactive oxygen species generation and cellular apoptosis, implying that SIRT3 might play an important neuroprotective role during early brain injury following SAH.

scholarly journals TAK1 mediates neuronal pyroptosis in early brain injury after subarachnoid hemorrhage

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Pengfei Xu ◽  
Chunrong Tao ◽  
Yuyou Zhu ◽  
Guoping Wang ◽  
Lingqi Kong ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Nlrp3 Inflammasome ◽  
Reactive Oxygen ◽  
Early Brain Injury ◽  
Potential Candidate ◽  
Oxygen Species

Abstract Background Innate immunity can facilitate early brain injury (EBI) following subarachnoid hemorrhage (SAH). Numerous studies suggest that pyroptosis could exacerbate extracellular immune responses by promoting secretion of inflammatory cytokines. Transforming growth factor-β-activated kinase 1 (TAK1) is a quintessential kinase that positively regulates inflammation through NF-κB and MAPK signaling cascades. However, the effects of TAK1 on neuroinflammation in EBI following SAH are largely unknown. Methods Two hundred and forty-six male C57BL/6J mice were subjected to the endovascular perforation model of SAH. A selective TAK1 inhibitor, 5Z-7-oxozeaenol (OZ) was administered by intracerebroventricular (i.c.v) injection at 30 min after SAH induction. To genetic knockdown of TAK1, small interfering RNA (siRNA) was i.c.v injected at 48 h before SAH induction. SAH grade, brain water content, BBB permeability, neurological score, western blot, real-time PCR, ELISA, transmission electron microscope, and immunofluorescence staining were performed. Long-term behavioral sequelae were evaluated by the rotarod and Morris water maze tests. Furthermore, OZ was added to the culture medium with oxyhemoglobin (OxyHb) to mimic SAH in vitro. The reactive oxygen species level was detected by DCFH-DA staining. Lysosomal integrity was assessed by Lyso-Tracker Red staining and Acridine Orange staining. Results The neuronal phosphorylated TAK1 expression was upregulated following SAH. Pharmacologic inhibition of TAK1 with OZ could alleviate neurological deficits, brain edema, and brain-blood barrier (BBB) disruption at 24 h after SAH. In addition, OZ administration restored long-term neurobehavioral function. Furthermore, blockade of TAK1 dampened neuronal pyroptosis by downregulating the N-terminal fragment of GSDMD (GSDMD-N) expression and IL-1β/IL-18 production. Mechanistically, both in vivo and in vitro, we demonstrated that TAK1 can induce neuronal pyroptosis through promoting nuclear translocation of NF-κB p65 and activating nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. TAK1 siRNA treatment mitigated SAH-induced neurobehavioral deficits and restrained phosphorylated NF-κB p65 expression and NLRP3 inflammasome activation. TAK1 blockade also ameliorated reactive oxygen species (ROS) production and prevented lysosomal cathepsin B releasing into the cytoplasm. Conclusions Our findings demonstrate that TAK1 modulates NLRP3-mediated neuronal pyroptosis in EBI following SAH. Inhibition of TAK1 may serve as a potential candidate to relieve neuroinflammatory responses triggered by SAH.

scholarly journals Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence

2019 ◽  
Author(s):  
Alberto Granzotto ◽  
Manuela Bomba ◽  
Vanessa Castelli ◽  
Riccardo Navarra ◽  
Noemi Massetti ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Cortical Neurons ◽  
De Novo ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Synaptic Activity ◽  
Oxygen Species

AbstractAlthough aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of de novo ceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as an in vitro model of cellular senescence. Our findings indicate that ‘aged’ neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca2+]i levels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca2+]i signaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.The results suggest that the de novo ceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

Роль оксида азота в реализации антиоксидантного эффекта неопиатного аналога лей-энкефалина в сердце новорожденных белых крыс

2019 ◽  
pp. 61-64
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Postnatal Period ◽  
Oxide System ◽  
No Synthase ◽  
Albino Rats ◽  
Oxygen Species ◽  
Control Parameters ◽  
Synthase Inhibitor

The eff ect of the non-opiate analog of leu-enkephalin (peptide NALE: Phe – D – Ala – Gly – Phe – Leu – Arg) on the reactive oxygen species generation in the heart of albino rats in the early postnatal period was studied. Peptide NALE was administered intraperitoneally in the dose of 100 μ/kg daily from 2 to 6 days of life. Reactive oxygen species generation was assessed by chemiluminescence in the heart homogenates of 7-day-old animals. Decreasing of reactive oxygen species generation nearly by 30 % and an increasing in antioxidant system activity by the 20-27 %, compared with the control parameters, were found. The antioxidant eff ect of peptide NALE is associated with the presence of the amino acid Arg in the structure of the peptide. An analogue of NALE peptide, devoid of Arg (peptide Phe – D – Ala – Gly – Phe – Leu – Gly), had a signifi cant lower antioxidant eff ect. The NO-synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in the dose 50 mg/kg, administered with NALE peptide, reduced the severity of the NALE antioxidant eff ect. The results of the study suggest that the pronounced antioxidant eff ect of NALE peptide in the heart of albino rats, at least in part, is due to the interaction with the nitric oxide system.

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