Excitotoxicity‐induced endocytosis confers drug targeting in cerebral ischemia

Vaslin, Anne; Puyal, Julien; Clarke, Peter G. H.

doi:10.1002/ana.21584

Cited by 22 publications

(29 citation statements)

References 39 publications

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“…This neuroprotective mechanism that we propose is also consistent with the link between neuronal cell surface-HSPGs (Litwack et al, 1994) and endocytic activity (Vaslin et al, 2009a), which are known to promote endosomal uptake of cationic CPPs (Nakase et al, 2007;Vaslin et al, 2009aVaslin et al, , 2011. It is also possible that other negatively charged cell surface receptors such as CSPGs and glycosphingolipids can promote cationic CPP endocytosis and neuroprotection.…”

Section: Proposed Neuroprotective Mechanism Of Action Used By Argininsupporting

confidence: 72%

“…Consequently, the lack of neuroprotection seen with a TAT fused mutant JNKI-1 peptide containing three alanine substitutions (RPKRPTAANAFPQVPRSQD-TAT) in cultured neurons exposed to NMDA excitotoxicity may well be due to the reduced endocytic traits of this peptide. In this context, the studies by Vaslin et al (2009aVaslin et al ( , 2011 suggest that neuronal endocytic uptake of the TAT-JNKI-1 peptide is an essential prerequisite for neuroprotection, a view reinforced by studies in our laboratory (Meloni et al, 2015). However, as discussed elsewhere, our view is that the endocytic process is the key to the neuroprotective mechanism and that the interaction of the TAT-JNKI-1 peptide with its cytoplasmic target (JIP scaffold protein) is unlikely to play a major role due to poor endosomal peptide escape and/or endosomal/ lysosomal peptide degradation.…”

Section: In Vivo Studiesmentioning

confidence: 98%

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Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

Meloni

Milani

Edwards

et al. 2015

Pharmacology & Therapeutics

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Several recent studies have demonstrated that TAT and other arginine-rich cell penetrating peptides (CPPs) have intrinsic neuroprotective properties in their own right. Examples, we have demonstrated that in addition to TAT, poly-arginine peptides (R8 to R18; containing 8-18 arginine residues) as well as some other arginine-rich peptides are neuroprotective in vitro (in neurons exposed to glutamic acid excitotoxicity and oxygen glucose deprivation) and in the case of R9 in vivo (after permanent middle cerebral artery occlusion in the rat). Based on several lines of evidence, we propose that this neuroprotection is related to the peptide's endocytosis-inducing properties, with peptide charge and arginine residues being critical factors. Specifically, we propose that during peptide endocytosis neuronal cell surface structures such as ion channels and transporters are internalised, thereby reducing calcium influx associated with excitotoxicity and other receptor-mediated neurodamaging signalling pathways. We also hypothesise that a peptide cargo can act synergistically with TAT and other arginine-rich CPPs due to potentiation of the CPPs endocytic traits rather than by the cargo-peptide acting directly on its supposedly intended intracellular target. In this review, we systematically consider a number of studies that have used CPPs to deliver neuroprotective peptides to the central nervous system (CNS) following stroke and other neurological disorders. Consequently, we critically review evidence that supports our hypothesis that neuroprotection is mediated by carrier peptide endocytosis. In conclusion, we believe that there are strong grounds to regard arginine-rich peptides as a new class of neuroprotective molecules for the treatment of a range of neurological disorders.

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Section: Proposed Neuroprotective Mechanism Of Action Used By Argininsupporting

confidence: 72%

Section: In Vivo Studiesmentioning

confidence: 98%

Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

Meloni

Milani

Edwards

et al. 2015

Pharmacology & Therapeutics

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“…In contrast, little is known about how NMDAR overactivation affects the levels of TrkB at the cell surface. Endocytosis is enhanced in excitotoxicity by a clathrin/dynamin‐mediated mechanism preceding neuronal death in vitro (Vaslin et al , ) or ischemia (Vaslin et al , ). Here, we demonstrate that a brief excitotoxic insult induces a strong cell surface decrease in TrkB‐FL previous to processing.…”

Section: Discussionmentioning

confidence: 99%

Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

et al. 2019

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Neuroprotective strategies aimed to pharmacologically treat stroke, a prominent cause of death, disability, and dementia, have remained elusive. A promising approach is restriction of excitotoxic neuronal death in the infarct penumbra through enhancement of survival pathways initiated by brain‐derived neurotrophic factor (BDNF). However, boosting of neurotrophic signaling after ischemia is challenged by downregulation of BDNF high‐affinity receptor, full‐length tropomyosin‐related kinase B (TrkB‐FL), due to calpain‐degradation, and, secondarily, regulated intramembrane proteolysis. Here, we have designed a blood–brain barrier (BBB) permeable peptide containing TrkB‐FL sequences (TFL 457 ) which prevents receptor disappearance from the neuronal surface, early induced after excitotoxicity. In this way, TFL 457 interferes TrkB‐FL cleavage by both proteolytic systems and increases neuronal viability via a PLCγ‐dependent mechanism. By preserving downstream CREB and MEF2 promoter activities, TFL 457 initiates a feedback mechanism favoring increased levels in excitotoxic neurons of critical prosurvival mRNAs and proteins. This neuroprotective peptide could be highly relevant for stroke therapy since, in a mouse ischemia model, it counteracts TrkB‐FL downregulation in the infarcted brain, efficiently decreases infarct size, and improves neurological outcome.

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“…Neurons on coverslips were transfected using Lipofectamine 2000 (Invitrogen, 11668-019) as described previously. 69 In brief, 2/3 of the medium was removed and replaced for 5 h by fresh Neurobasal medium (Life Technologies, 21103-049) plus transfection mix with the tandem mRFP-GFP-LC3-expressing plasmid ptfLC3 (Addgene, 21074) ( Lactate dehydrogenase release Cell death was assayed by measurement of LDH released in the medium using the Cytotox 96 nonradioactive cytotoxicity assay kit (Promega, G1780) as previously described. 66 LDH measurements were normalized with respect to the values with control vector 6 h after the KaHx treatment condition.…”

Section: Mrfp-gfp-lc3 Plasmid Transfection and Quantificationmentioning

confidence: 99%

Involvement of autophagy in hypoxic-excitotoxic neuronal death

et al. 2014

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Excitotoxicity‐induced endocytosis confers drug targeting in cerebral ischemia

Abstract: Excitotoxicity-induced endocytosis is the main entry route for protective TAT peptides and targets selectively the neurons that need to be protected.

Cited by 22 publications

References 39 publications

Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

Prevention of excitotoxicity‐induced processing of BDNF receptor TrkB‐FL leads to stroke neuroprotection

Involvement of autophagy in hypoxic-excitotoxic neuronal death

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