Assessment of the neuroprotective effects of arginine-rich protamine peptides, poly-arginine peptides (R12-Cyclic, R22) and arginine–tryptophan-containing peptides following in vitro excitotoxicity and/or permanent middle cerebral artery occlusion in rats

Bruno P. Meloni, Diego Milani, Jane L. Cross, Vince W. Clark, Adam B. Edwards, Ryan S. Anderton, David J. Blacker, Neville W. Knuckey

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14 Citations (Scopus)

Abstract

We have demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties with arginine content and peptide positive charge being particularly critical for neuroprotective efficacy. In addition, the presence of other amino acids within arginine-rich peptides, as well as chemical modifications, peptide length and cell-penetrating properties also influence the level of neuroprotection. Against this background, we have examined the neuroprotective efficacy of arginine-rich protamine peptides, a cyclic (R12-c) poly-arginine peptide and a R22 poly-arginine peptide, as well as arginine peptides containing tryptophan or other amino acids (phenylalanine, tyrosine, glycine or leucine) in in vitro glutamic acid excitotoxicity and in vivo rat permanent middle cerebral artery occlusion models of stroke. In vitro studies demonstrated that protamine and poly-arginine peptides (R12-c, R22) were neuroprotective. Arginine–tryptophan-containing peptides were highly neuroprotective, with R12W8a being the most potent arginine-rich peptide identified in our laboratory. Peptides containing phenylalanine or tyrosine substituted in place of tryptophan in R12W8a were also highly neuroprotective, whereas leucine, and in particular glycine substitutions, decreased peptide efficacy. In vivo studies with protamine administered intravenously at 1000 nmol/kg 30 min after MCAO significantly reduced infarct volume and cerebral oedema by 22.5 and 38.6%, respectively. The R12W8a peptide was highly toxic when administered intravenously at 300 or 100 nmol/kg and ineffective at reducing infarct volume when administered at 30 nmol/kg 30 min after MCAO, unlike R18 (30 nmol/kg), which significantly reduced infarct volume by 20.4%. However, both R12W8a and R18 significantly reduced cerebral oedema by 19.8 and 42.2%, respectively. Protamine, R12W8a and R18 also reduced neuronal glutamic acid-induced calcium influx. These findings further highlight the neuroprotective properties of arginine-rich peptides and support the view that they represent a new class of neuroprotective agent.  Springer Science+Business Media New York 2017

Original languageEnglish
Pages (from-to)271-285
Number of pages15
JournalNeuroMolecular Medicine
Volume19
Issue number2-3
DOIs
Publication statusPublished - Sep 2017

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Cyclic Peptides
Protamines
Middle Cerebral Artery Infarction
Neuroprotective Agents
Arginine
Peptides
Brain Edema
Phenylalanine
Leucine
Tryptophan
In Vitro Techniques
Glycine
Tyrosine
Glutamic Acid
Cell-Penetrating Peptides
Amino Acids
Poisons

Cite this

@article{24a082c4c5ca4aacb42c82f65a0bdeff,
title = "Assessment of the neuroprotective effects of arginine-rich protamine peptides, poly-arginine peptides (R12-Cyclic, R22) and arginine–tryptophan-containing peptides following in vitro excitotoxicity and/or permanent middle cerebral artery occlusion in rats",
abstract = "We have demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties with arginine content and peptide positive charge being particularly critical for neuroprotective efficacy. In addition, the presence of other amino acids within arginine-rich peptides, as well as chemical modifications, peptide length and cell-penetrating properties also influence the level of neuroprotection. Against this background, we have examined the neuroprotective efficacy of arginine-rich protamine peptides, a cyclic (R12-c) poly-arginine peptide and a R22 poly-arginine peptide, as well as arginine peptides containing tryptophan or other amino acids (phenylalanine, tyrosine, glycine or leucine) in in vitro glutamic acid excitotoxicity and in vivo rat permanent middle cerebral artery occlusion models of stroke. In vitro studies demonstrated that protamine and poly-arginine peptides (R12-c, R22) were neuroprotective. Arginine–tryptophan-containing peptides were highly neuroprotective, with R12W8a being the most potent arginine-rich peptide identified in our laboratory. Peptides containing phenylalanine or tyrosine substituted in place of tryptophan in R12W8a were also highly neuroprotective, whereas leucine, and in particular glycine substitutions, decreased peptide efficacy. In vivo studies with protamine administered intravenously at 1000 nmol/kg 30 min after MCAO significantly reduced infarct volume and cerebral oedema by 22.5 and 38.6{\%}, respectively. The R12W8a peptide was highly toxic when administered intravenously at 300 or 100 nmol/kg and ineffective at reducing infarct volume when administered at 30 nmol/kg 30 min after MCAO, unlike R18 (30 nmol/kg), which significantly reduced infarct volume by 20.4{\%}. However, both R12W8a and R18 significantly reduced cerebral oedema by 19.8 and 42.2{\%}, respectively. Protamine, R12W8a and R18 also reduced neuronal glutamic acid-induced calcium influx. These findings further highlight the neuroprotective properties of arginine-rich peptides and support the view that they represent a new class of neuroprotective agent.  Springer Science+Business Media New York 2017",
keywords = "Excitotoxicity, Middle cerebral artery occlusion (MCAO), Neuroprotection, Poly-arginine, Protamine, Stroke, Tryptophan",
author = "Meloni, {Bruno P.} and Diego Milani and Cross, {Jane L.} and Clark, {Vince W.} and Edwards, {Adam B.} and Anderton, {Ryan S.} and Blacker, {David J.} and Knuckey, {Neville W.}",
year = "2017",
month = "9",
doi = "10.1007/s12017-017-8441-2",
language = "English",
volume = "19",
pages = "271--285",
journal = "NeuroMolecular Medicine",
issn = "1535-1084",
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TY - JOUR

T1 - Assessment of the neuroprotective effects of arginine-rich protamine peptides, poly-arginine peptides (R12-Cyclic, R22) and arginine–tryptophan-containing peptides following in vitro excitotoxicity and/or permanent middle cerebral artery occlusion in rats

AU - Meloni, Bruno P.

AU - Milani, Diego

AU - Cross, Jane L.

AU - Clark, Vince W.

AU - Edwards, Adam B.

AU - Anderton, Ryan S.

AU - Blacker, David J.

AU - Knuckey, Neville W.

PY - 2017/9

Y1 - 2017/9

N2 - We have demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties with arginine content and peptide positive charge being particularly critical for neuroprotective efficacy. In addition, the presence of other amino acids within arginine-rich peptides, as well as chemical modifications, peptide length and cell-penetrating properties also influence the level of neuroprotection. Against this background, we have examined the neuroprotective efficacy of arginine-rich protamine peptides, a cyclic (R12-c) poly-arginine peptide and a R22 poly-arginine peptide, as well as arginine peptides containing tryptophan or other amino acids (phenylalanine, tyrosine, glycine or leucine) in in vitro glutamic acid excitotoxicity and in vivo rat permanent middle cerebral artery occlusion models of stroke. In vitro studies demonstrated that protamine and poly-arginine peptides (R12-c, R22) were neuroprotective. Arginine–tryptophan-containing peptides were highly neuroprotective, with R12W8a being the most potent arginine-rich peptide identified in our laboratory. Peptides containing phenylalanine or tyrosine substituted in place of tryptophan in R12W8a were also highly neuroprotective, whereas leucine, and in particular glycine substitutions, decreased peptide efficacy. In vivo studies with protamine administered intravenously at 1000 nmol/kg 30 min after MCAO significantly reduced infarct volume and cerebral oedema by 22.5 and 38.6%, respectively. The R12W8a peptide was highly toxic when administered intravenously at 300 or 100 nmol/kg and ineffective at reducing infarct volume when administered at 30 nmol/kg 30 min after MCAO, unlike R18 (30 nmol/kg), which significantly reduced infarct volume by 20.4%. However, both R12W8a and R18 significantly reduced cerebral oedema by 19.8 and 42.2%, respectively. Protamine, R12W8a and R18 also reduced neuronal glutamic acid-induced calcium influx. These findings further highlight the neuroprotective properties of arginine-rich peptides and support the view that they represent a new class of neuroprotective agent.  Springer Science+Business Media New York 2017

AB - We have demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties with arginine content and peptide positive charge being particularly critical for neuroprotective efficacy. In addition, the presence of other amino acids within arginine-rich peptides, as well as chemical modifications, peptide length and cell-penetrating properties also influence the level of neuroprotection. Against this background, we have examined the neuroprotective efficacy of arginine-rich protamine peptides, a cyclic (R12-c) poly-arginine peptide and a R22 poly-arginine peptide, as well as arginine peptides containing tryptophan or other amino acids (phenylalanine, tyrosine, glycine or leucine) in in vitro glutamic acid excitotoxicity and in vivo rat permanent middle cerebral artery occlusion models of stroke. In vitro studies demonstrated that protamine and poly-arginine peptides (R12-c, R22) were neuroprotective. Arginine–tryptophan-containing peptides were highly neuroprotective, with R12W8a being the most potent arginine-rich peptide identified in our laboratory. Peptides containing phenylalanine or tyrosine substituted in place of tryptophan in R12W8a were also highly neuroprotective, whereas leucine, and in particular glycine substitutions, decreased peptide efficacy. In vivo studies with protamine administered intravenously at 1000 nmol/kg 30 min after MCAO significantly reduced infarct volume and cerebral oedema by 22.5 and 38.6%, respectively. The R12W8a peptide was highly toxic when administered intravenously at 300 or 100 nmol/kg and ineffective at reducing infarct volume when administered at 30 nmol/kg 30 min after MCAO, unlike R18 (30 nmol/kg), which significantly reduced infarct volume by 20.4%. However, both R12W8a and R18 significantly reduced cerebral oedema by 19.8 and 42.2%, respectively. Protamine, R12W8a and R18 also reduced neuronal glutamic acid-induced calcium influx. These findings further highlight the neuroprotective properties of arginine-rich peptides and support the view that they represent a new class of neuroprotective agent.  Springer Science+Business Media New York 2017

KW - Excitotoxicity

KW - Middle cerebral artery occlusion (MCAO)

KW - Neuroprotection

KW - Poly-arginine

KW - Protamine

KW - Stroke

KW - Tryptophan

UR - http://www.scopus.com/inward/record.url?scp=85019564961&partnerID=8YFLogxK

U2 - 10.1007/s12017-017-8441-2

DO - 10.1007/s12017-017-8441-2

M3 - Article

VL - 19

SP - 271

EP - 285

JO - NeuroMolecular Medicine

JF - NeuroMolecular Medicine

SN - 1535-1084

IS - 2-3

ER -