okadaic-acid and glycyl-prolyl-glutamic-acid

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.

Topics: Administration, Oral; Animals; Apoptosis; Blood Chemical Analysis; Brain; Disease Models, Animal; Female; Infarction, Middle Cerebral Artery; Infusions, Intravenous; Male; Microdialysis; Neuroprotective Agents; Okadaic Acid; Oligopeptides; Rats; Rats, Sprague-Dawley; Stroke

The synthesis of nine GPE* analogues, wherein the alpha-carboxylic acid group of glutamic acid has been modified, is described by coupling readily accessible N-benzyloxycarbonyl-glycyl-L-proline 2 with various analogues of glutamic acid. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glutamate residue on the observed neuroprotective properties of the endogenous tripeptide GPE.

Topics: Animals; Cells, Cultured; Corpus Striatum; Female; Glutamic Acid; Models, Chemical; Molecular Structure; Neurons; Neuroprotective Agents; Okadaic Acid; Oligopeptides; Rats; Rats, Wistar

The synthesis of eight GPE* analogues, wherein the gamma-carboxylic moiety of the glutamic residue has been modified, is described by coupling readily accessible N-benzyloxycarbonyl-glycyl-L-proline with various analogues of glutamic acid. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glutamate residue on the observed neuroprotective properties of the endogenous tripeptide GPE.

Topics: Animals; Cells, Cultured; Corpus Striatum; Female; Glutamic Acid; Models, Chemical; Molecular Structure; Neurons; Neuroprotective Agents; Okadaic Acid; Oligopeptides; Rats; Rats, Wistar

The synthesis of 10 G*PE analogues, wherein the glycine residue has been modified, is described by coupling readily accessible dibenzyl-L-prolyl-L-glutamate 2 with various analogues of glycine. Pharmacological evaluation of the novel compounds was undertaken to further understand the role of the glycine residue on the observed neuroprotective properties of the endogenous tripeptide GPE.

Topics: Animals; Cells, Cultured; Corpus Striatum; Female; Glutamic Acid; Glycine; Models, Chemical; Molecular Structure; Neurons; Neuroprotective Agents; Okadaic Acid; Oligopeptides; Rats; Rats, Wistar