title: NNZ-2566: a Gly-Pro-Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke.
abstract: The N-terminal cleavage product of human insulin-like growth factor-1 (IGF-1) in the brain is the tripeptide molecule Glypromate (Gly-Pro-Glu). Glypromate has demonstrated neuroprotective effects in numerous in vitro and in vivo models of brain injury and is in clinical trials for the prevention of cognitive impairment following cardiac surgery. NNZ-2566 is a structural analogue of Glypromate, resulting from alpha-methylation of the proline moiety, which has improved the elimination half-life and oral bioavailability over the parent peptide. In vivo, NNZ-2566 reduces injury size in rats subjected to focal stroke. An intravenous infusion of NNZ-2566 of 4 h duration (3-10 mg/kg/h), initiated 3 h after endothelin-induced middle-cerebral artery constriction, significantly reduced infarct area as assessed on day 5. Neuroprotective efficacy in the MCAO model was also observed following oral administration of the drug (30-60 mg/kg), when formulated as a microemulsion. In vitro, NNZ-2566 significantly attenuates apoptotic cell death in primary striatal cultures, suggesting attenuation of apoptosis is one mechanism of action underlying its neuroprotective effects. NNZ-2566 is currently in clinical trials for the treatment of cognitive deficits following traumatic brain injury, and these data further support the development of the drug as a neuroprotective agent for acute brain injury.
authors.affiliation: Neuren Pharmaceuticals Ltd, 57 Wellington Street, Freemans Bay, Auckland 1011, New Zealand. mbickerdike@neurenpharma.com
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bickerdike
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Thomas
authors.forename: David C
authors.initials: DC
authors.lastname: Batchelor
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Sirimanne
authors.forename: Wing
authors.initials: W
authors.lastname: Leong
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.forename: Frank
authors.initials: F
authors.lastname: Sieg
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Wen
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harris
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gluckman
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D051381:Rats; D000284:Administration, Oral; D017209:Apoptosis / Q000187:drug effects; D001774:Blood Chemical Analysis; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D007262:Infusions, Intravenous; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019319:Okadaic Acid / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy; D005971:Glutamates
chemical_list: C062053:glycyl-prolyl-glutamic acid; D018696:Neuroprotective Agents; D019319:Okadaic Acid; D009842:Oligopeptides; C000656362:trofinetide; D005971:Glutamates