Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

MacDougall, Gabriella; Anderton, Ryan S.; Mastaglia, Frank; Knuckey, Neville W.; Meloni, Bruno P.

doi:10.1016/j.nbd.2018.09.010

Cited by 36 publications

(25 citation statements)

References 290 publications

(270 reference statements)

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“…A variety of mitochondrial targeting peptides can be used in the treatment of diseases [ 22 , 23 ]. The new beneficial effect of MitoQ on renal tubular injury in diabetic kidney disease was demonstrated by in vitro and in vivo models.…”

Section: Discussionmentioning

confidence: 99%

The mitochondrial-targeted peptide SBT-20 ameliorates inflammation and oxidative stress in chronic renal failure

Sun

Wang

et al. 2020

Aging

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Chronic renal failure (CRF) is the final outcome of the development of chronic kidney disease with different causes. Although CRF is a common clinical disease, its pathogenesis remains to be improved. SBT-20 belongs to a class of cell-permeable peptides that target the inner mitochondrial membrane, reduce reactive oxygen species (ROS), normalize electron transport chain function, and ATP generation. Our experiment was to evaluate whether SBT-20 affected the oxidative stress and inflammatory process of CRF. The levels of ROS production, mitochondrial membrane potential, NF- κB-p65, TNF-α, Drp1, and mfn2 were measured before and after SBT-20 treatment. We observed that SBT-20 treatment inhibited H2O2-induced mitochondrial ROS production. SBT-20 could also restore the mitochondrial membrane potential and reduce the elevated levels of NF-κB-p65 and TNF-α in HK-2 cells. In vivo , the renal function of CRF mice recovered after treating with SBT-20, the levels of necrotic cells and inflammation decreased, and the morphology of mitochondria recovered. The results showed that SBT-20 had a protective effect on CRF by reducing oxidative stress, inflammation progression via down-regulating of NF-κB-p65, TNF-α, and Drp1 and upregulating of Mfn2. These data support SBT-20 could be used as a potential preparation for CRF.

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Section: Discussionmentioning

confidence: 99%

The mitochondrial-targeted peptide SBT-20 ameliorates inflammation and oxidative stress in chronic renal failure

Sun

Wang

et al. 2020

Aging

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“…In recent years, CARPs have emerged as a novel class of potential neuroprotective therapeutics for a broad range of acute brain injuries and chronic neurodegenerative disorders. These CARPs include short-chained polyarginine peptides [11,13,27], SS-peptides [28,29], APOE-derived peptides [27,30], and TAT-fused peptides, including TAT-NR2B9c (NA-1) and JNK1-TAT [11,31]. Such CARPs have been shown to exert their neuroprotective action through a variety of targets, which include structural and functional preservation of mitochondria [32], reduced ROS generation [33], inhibition of protein aggregation [34], modulation of glutamate or calcium ion receptors (excitotoxicity/calcium influx) [35], and activation of pro-survival signaling [36,37].…”

Section: Discussionmentioning

confidence: 99%

“…Proteomic analysis also revealed that R18 preserved protein expression profiles pertaining to mitochondrial bioenergetics and structural integrity. Mitochondria are central mediators of intracellular calcium signaling events during excitotoxicity, and as such, are considered the "judge, jury, and executioner" of the cell [31,43].…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of cortical neuronal cultures treated with poly-arginine peptide-18 (R18) and exposed to glutamic acid excitotoxicity

et al. 2019

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Poly-arginine peptide-18 (R18) has recently emerged as a highly effective neuroprotective agent in experimental stroke models, and is particularly efficacious in protecting cortical neurons against glutamic acid excitotoxicity. While we have previously demonstrated that R18 can reduce excitotoxicity-induced neuronal calcium influx, other molecular events associated with R18 neuroprotection are yet to investigated. Therefore, in this study we were particularly interested in protein expression changes in R18 treated neurons subjected to excitotoxicity. Proteomic analysis was used to compare protein expression patterns in primary cortical neuronal cultures subjected to: (i) R18-treatment alone (R18); (ii) glutamic acid excitotoxic injury (Glut); (iii) R18-treatment and glutamic acid injury (R18 + Glut); (iv) no treatment (Cont). Whole cell lysates were harvested 24 h post-injury and subjected to quantitative proteomic analysis (iTRAQ), coupled with liquid chromatography-tandem mass spectrometry (LC-MS/ MS) and subsequent bioinformatic analysis of differentially expressed proteins (DEPs). Relative to control cultures, R18, Glut, and R18 + Glut treatment resulted in the detection of 5, 95 and 14 DEPs respectively. Compared to Glut alone, R18 + Glut revealed 98 DEPs, including 73 proteins whose expression was also altered by treatment with Glut and/or R18 alone, as well as 25 other uniquely regulated proteins. R18 treatment reversed the up-or down-regulation of all 73 Glut-associated DEPs, which included proteins involved in mitochondrial integrity, ATP generation, mRNA processing and protein translation. Analysis of protein-protein interactions of the 73 DEPs showed they were primarily associated with mitochondrial respiration, proteasome activity and protein synthesis, transmembrane trafficking, axonal growth and neuronal differentiation, and carbohydrate metabolism. Identified protein pathways associated with proteostasis and energy metabolism, and with pathways involved in neurodegeneration. Collectively, the findings indicate that R18 neuroprotection following excitotoxicity is associated with preservation of neuronal protein profiles, and differential protein expression that assists in maintaining mitochondrial function and energy production, protein homeostasis, and membrane trafficking.

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“…Apoptosis is considered a vital component of the development of cerebral I/R injury [30]. Excessive mitochondrial fission promotes mitochondrial outer membrane permeability and increases Cyto c release, subsequently activating the apoptotic cascade reaction and eventually aggravating neurological damage [13,31]. Moreover, in a study by Wang et al [32], adenoviral Fis1, which can induce Fis1 overexpression, increased mitochondrial fission and apoptosis, whereas Fis1 knockdown attenuated mitochondrial fission and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Selective brain hypothermia ameliorates focal cerebral ischemia-reperfusion injury via inhibiting Fis1 in rats

Tang

Chen

Sun

et al. 2019

Preprint

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13Mitochondrial immoderate fission induces neuronal apoptosis following focal cerebral 14 ischemia-reperfusion (I/R) injury. With fewer complications, selective brain 15 hypothermia (SBH) is considered an effective treatment against neuronal injury after 16 stroke. However, the specific mechanism by which SBH influences mitochondrial 17 fission remains unknown. Mitochondrial fission 1 protein (Fis1), a key factor of the 18 mitochondrial fission system, regulates mitochondrial dynamics. This study aimed to 19 investigate whether SBH regulates Fis1 expression in focal cerebral I/R injury. In this 20 study, rat middle cerebral artery occlusion (MCAO) models were established. After 2 21 h of occlusion, cold saline or normal saline was pumped into rats in different groups 22 through the carotid artery, followed by restoration of blood perfusion. Cortical and 23 rectal temperatures showed that the cold saline treatment achieved SBH. Cerebral I/R 24 injury increased neurological deficit scores(NDS); neuronal apoptosis; Fis1 protein 25 and mRNA expression; cytosolic cytochrome c (cyto-Cyto c) protein expression at 6, 26 24 and 48 h postreperfusion; and cerebral infarct volumes at 24 h postreperfusion. 27 Interestingly, SBH inhibited Fis1 protein and mRNA expression, blocked cyto-Cyto c 28 protein expression, preserved neuronal cell integrity, and reduced neuronal apoptosis. 29 However, normal saline treatment rarely resulted in positive outcomes. Based on 30 these results, SBH inhibited Fis1 expression, thus ameliorating focal cerebral I/R 31 injury in rats.32 3 33 Introduction 34 Stroke is one of the leading causes of death and disability in the world [1-3]. Ischemic 35 stroke caused by cerebral thrombosis or endovascular embolization accounts for a 36 major portion of strokes. Early restoration of blood perfusion is the most effective 37 treatment for stroke; this treatment provides nutrients and oxygen and removes toxic 38 metabolites [4,5]. However, vessel recanalization often exacerbates the existing tissue 39 damage [6,7]; thus, this condition is called cerebral ischemia-reperfusion (I/R) injury. 40 Recent studies have suggested that morphological changes in mitochondria might be 41 relevant to I/R injury [8,9]. Within the cell, mitochondria exist in an ever-changing 42 dynamic state-constant fission and fusion-to form mitochondrial networks and 43 maintain cellular physiological function and survival [10]. Notably, growing evidence 44 has indicated that I/R injury can break this balance to induce neuronal apoptosis 45 [11-13]. Mitochondrial fission protein 1 (Fis1), a 16-kDa protein anchored to the outer 46 membrane of the mitochondria, mediates mitochondrial fission by recruiting 47 cytoplasmic dynamin-related protein1 (Drp1) into the mitochondrial outer membrane 48 [14]. Overexpression of Fis1 increases the frequency of mitochondrial fission, 49 subsequently increasing the release of Cyto c and disrupting mitochondrial membrane 50 potential, thus inducing neuronal apoptosis [15]. In addition, in cells with th...

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Mitochondria and neuroprotection in stroke: Cationic arginine-rich peptides (CARPs) as a novel class of mitochondria-targeted neuroprotective therapeutics

Cited by 36 publications

References 290 publications

The mitochondrial-targeted peptide SBT-20 ameliorates inflammation and oxidative stress in chronic renal failure

The mitochondrial-targeted peptide SBT-20 ameliorates inflammation and oxidative stress in chronic renal failure

Proteomic analysis of cortical neuronal cultures treated with poly-arginine peptide-18 (R18) and exposed to glutamic acid excitotoxicity

Selective brain hypothermia ameliorates focal cerebral ischemia-reperfusion injury via inhibiting Fis1 in rats

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