Poly-arginine-18 peptides do not exacerbate bleeding, or improve functional outcomes following collagenase-induced intracerebral hemorrhage in the rat

Cationic arginine-rich peptides (CARPs) have demonstrated neuroprotective and/or behavioural efficacy in ischemic and hemorrhagic stroke and traumatic brain injury models. Therefore, in this study we investigated the safety and neuroprotective efficacy of the CARPs poly-arginine-18 (R18; 18-mer of a...

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Bibliographic Details
Published in:PloS one 2019-11, Vol.14 (11), p.e0224870-e0224870
Main Authors: Liddle, Lane, Reinders, Ryan, South, Samantha, Blacker, David, Knuckey, Neville, Colbourne, Frederick, Meloni, Bruno
Format: Article
Language:English
Subjects:
Administration, Intravenous
Animals
Arginine
Biology and Life Sciences
Bleeding
Brain injuries
Brain research
Carps
Cerebral Hemorrhage - chemically induced
Cerebral Hemorrhage - drug therapy
Collagen
Collagenase
Collagenases - adverse effects
Disease Models, Animal
Dose-Response Relationship, Drug
Edema
Enantiomers
Head injuries
Hematoma
Hemorrhage
Injection
Intracerebral hemorrhage
Intravenous administration
Ischemia
Kinases
Lesions
Male
Medicine and Health Sciences
Neurological disorders
Neuroprotection
Neuroprotective Agents - administration & dosage
Neuroprotective Agents - pharmacology
Neurosurgery
Peptides
Peptides - administration & dosage
Peptides - pharmacology
Rats
Rats, Sprague-Dawley
Recovery of function
Recovery of Function - drug effects
Research and Analysis Methods
Safety
Safety regulations
Statistical analysis
Stroke
Studies
Traumatic brain injury
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Summary:Cationic arginine-rich peptides (CARPs) have demonstrated neuroprotective and/or behavioural efficacy in ischemic and hemorrhagic stroke and traumatic brain injury models. Therefore, in this study we investigated the safety and neuroprotective efficacy of the CARPs poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer R18D given in the acute bleeding phase in an intracerebral hemorrhage (ICH) model. One hundred and fifty-eight male Sprague-Dawley rats received collagenase-induced ICH. Study 1 examined various doses of R18D (30, 100, 300, or 1000 nmol/kg) or R18 (100, 300, 1000 nmol/kg) administered intravenously 30 minutes post-collagenase injection on hemorrhage volume 24 hours after ICH. Study 2 examined R18D (single intravenous dose) or R18 (single intravenous dose, plus 6 daily intraperitoneal doses) at 300 or 1000 nmol/kg commencing 30 minutes post-collagenase injection on behavioural outcomes (Montoya staircase test, and horizontal ladder test) in the chronic post-ICH period. A histological assessment of tissue loss was assessed using a Nissl stain at 28 days after ICH. When administered during ongoing bleeding, neither R18 or R18D exacerbated hematoma volume or worsened functional deficits. Lesion volume assessment at 28 days post-ICH was not reduced by the peptides; however, animals treated with the lower R18D 300 nmol/kg dose, but not with the higher 1000 nmol/kg dose, demonstrated a statistically increased lesion size compared to saline treated animals. Overall, both R18 and R18D appeared to be safe when administered during a period of ongoing bleeding following ICH. Neither peptide appears to have any statistically significant effect in reducing lesion volume or improving functional recovery after ICH. Additional studies are required to further assess dose efficacy and safety in pre-clinical ICH studies.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0224870