Neuroprotective efficacy of poly-arginine R18 and NA-1 (TAT-NR2B9c) peptides following transient middle cerebral artery occlusion in the rat

Milani, Diego; Cross, Jane L.; Anderton, Ryan S.; Blacker, David; Knuckey, Neville W.; Meloni, Bruno P.

doi:10.1016/j.neures.2016.09.002

Cited by 47 publications

(43 citation statements)

References 48 publications

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“…perinatal hypoxia-ischaemia, and also reduce the severity of traumatic brain injury [162,[265][266][267][268][269], further confirming the efficacy of CARPs in a pre-clinical stroke setting.…”

Section: Accepted Manuscriptmentioning

confidence: 83%

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

MacDougall

Anderton

Mastaglia

et al. 2019

Neurobiology of Disease

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Stroke is the second leading cause of death globally and represents a major cause of devastating long-term disability. Despite sustained efforts to develop clinically effective neuroprotective therapies, presently there is no clinically available neuroprotective agent for stroke. As a central mediator of neurodamaging events in stroke, mitochondria are recognised as a critical neuroprotective target, and as such, provide a focus for developing mitochondrial-targeted therapeutics. In recent years, cationic arginine-rich peptides (CARPs) have been identified as a novel class of neuroprotective agent with several demonstrated mechanisms of action, including their ability to target mitochondria and exert positive effects on the organelle. This review provides an overview on neuronal mitochondrial dysfunction in ischaemic stroke pathophysiology and highlights the potential beneficial effects of CARPs on mitochondria in the ischaemic brain following stroke.

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Section: Accepted Manuscriptmentioning

confidence: 83%

“…It is noteworthy in this regard that based on studies from our and other laboratories, other CARPs including polyarginine peptides (e.g. R18) display even greater neuroprotective efficacy than NA-1 in stroke and related neuronal injury models [162,257,264,265,267].…”

Section: Tat and Other Cationic Arginine-rich Cpp-fused Neuroprotectimentioning

confidence: 86%

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

MacDougall

Anderton

Mastaglia

et al. 2019

Neurobiology of Disease

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“…Our laboratory has also demonstrated that CARPs and in particular the poly-arginine peptide R18 are neuroprotective in in vivo experimental brain ischemic and/or hypoxic injury models [18,20,21,22,24,26,27,29], and that CARPs can reduce neuronal cell surface glutamate receptor levels and excitotoxic calcium influx [19,22,23,25,27,28]. As highlighted previously [19], based on our findings, we have proposed that the neuroprotective properties of most, if not all, putative neuroprotective peptides fused to cationic CPPs (e.g., TAT, R9 and penetratin), as well as other CARPs, are determined by the arginine content and positive charge of the peptide, with potency also influenced by other amino acid residues (e.g., lysine, tryptophan and phenylalanine) [19,29].…”

Section: Neuroprotective Peptides and Their Therapeutic Applicatiomentioning

confidence: 99%

“…R18 (RRRRRRRRRRRRRRRRRR; net charge +18) and its D-enantiomer (rrrrrrrrrrrrrrrrrr; net charge +18) is an 18-amino acid peptide and has been demonstrated to have potent neuroprotective properties in various in vitro and in vivo stroke related injury models [18,24,26,29]. Moreover, we have recently demonstrated for the first time that R18 and R18D (30, 100, 300 and 1000 nmol/kg; IP), administered immediately after hypoxia, reduced cerebral infarct volume and improved behavioral outcomes at 48 h post-HI [22].…”

Section: Neuroprotective Peptides and Their Therapeutic Applicatiomentioning

confidence: 99%

“…However, several years ago, our and other laboratories demonstrated that the TAT peptide has modest intrinsic neuroprotective properties in its own right [12,13,14,15,16,17]. We subsequently demonstrated that other cationic arginine-rich peptides [CARPs; e.g., penetratin, protamine, sodium calcium exchanger inhibitory peptide (XIP), poly-arginine peptides (e.g., R9, R12 and R18; R indicates amino acid arginine and number indicates mer)], possess potent neuroprotective properties in both in vitro and animal models of cerebral ischemia and/or hypoxia [12,18,19,20,21,22,23,24,25,26,27,28,29], and demonstrated that the arginine content and peptide positive charge are critical determinants of neuroprotection [19,27,28]. …”

Section: Introductionmentioning

confidence: 99%

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Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs)

et al. 2018

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Perinatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of mortality and morbidity in neonates, with survivors suffering significant neurological sequelae including cerebral palsy, epilepsy, intellectual disability and autism spectrum disorders. While hypothermia is used clinically to reduce neurological injury following HIE, it is only used for term infants (>36 weeks gestation) in tertiary hospitals and improves outcomes in only 30% of patients. For these reasons, a more effective and easily administrable pharmacological therapeutic agent, that can be used in combination with hypothermia or alone when hypothermia cannot be applied, is urgently needed to treat pre-term (≤36 weeks gestation) and term infants suffering HIE. Several recent studies have demonstrated that cationic arginine-rich peptides (CARPs), which include many cell-penetrating peptides [CPPs; e.g., transactivator of transcription (TAT) and poly-arginine-9 (R9; 9-mer of arginine)], possess intrinsic neuroprotective properties. For example, we have demonstrated that poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer (R18D) are neuroprotective in vitro following neuronal excitotoxicity, and in vivo following perinatal hypoxia-ischemia (HI). In this paper, we review studies that have used CARPs and other peptides, including putative neuroprotective peptides fused to TAT, in animal models of perinatal HIE. We critically evaluate the evidence that supports our hypothesis that CARP neuroprotection is mediated by peptide arginine content and positive charge and that CARPs represent a novel potential therapeutic for HIE.

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Advanced Functional Materials and Cell‐Based Therapies for the Treatment of Ischemic Stroke and Postischemic Stroke Effects

Tapeinos

Larrañaga

Tomatis

et al. 2019

Adv Funct Materials

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Ischemic stroke is considered one of the most threatening neurological disorders with high percentages of mortality and morbidity worldwide. Although in recent years, several nanotechnological advances have improved the survival rates, severe untreated poststroke side‐effects continue to significantly influence the way of life of many. Tissue plasminogen activator and mechanical thrombectomy are considered the gold standards for the treatment of acute cerebral ischemia. These, however, fail to improve postischemic disorders. Herein, after a brief description of the pathophysiology of ischemic stroke and the following biochemical cascade, the most recent biomaterial and cell‐based strategies are reviewed for its treatment. Other therapeutics that have been proposed not only for the treatment of cerebral ischemia but also for the regeneration of the infarcted brain that is responsible for a variety of disorders, including cognitive, motor, and speech problems are also presented. Finally, a few reported studies on diagnostic and theranostic nanostructures are also provided.

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Neuroprotective efficacy of poly-arginine R18 and NA-1 (TAT-NR2B9c) peptides following transient middle cerebral artery occlusion in the rat

Cited by 47 publications

References 48 publications

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

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

Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs)

Advanced Functional Materials and Cell‐Based Therapies for the Treatment of Ischemic Stroke and Postischemic Stroke Effects

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