Frank Sieg

NNZ-2566: A Gly–Pro–Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke

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.

Regulation of trophoblast migration and survival by a novel neural regeneration peptide

Although placental trophoblast migration is tightly controlled in an autocrine/paracrine manner, the nature of chemoattractive factors facilitating and directing this biological activity remains largely elusive. Neural regeneration peptides (NRP), a recently discovered peptide family, stimulate neuronal migration, differentiation and survival of post-natal neurons within the murine central nervous system. Based on the neural-repair related activities of these peptides and parallels between neuronal and placental cell behaviour patterns, this study postulated that they play a role in placental development, in particular trophoblast migration and survival and investigated the role of a newly discovered NRP motif (NNZ-4920), which exhibits about 70% homology to the mouse NRP motif sequence and is homologous to a 13-mer fragment within the N-terminus of human CAPS2, in trophoblast migration and survival regulation. NNZ-4920 significantly enhanced trophoblast migration by 51% (P<0.01) compared with controls and protected against stress induced by serum withdrawal and tumour necrosis factor-alpha/interferon-gamma treatment, at femtomolar concentrations, with efficacy similar to epidermal growth factor. CAPS2 expression was detected in purified term trophoblast and decidual cells. In conclusion, the placenta may be a source of NRP-related gene expression. Its encoded peptide products exert biological effects on term trophoblast migration and survival in vitro.