Development of neurotrophic peptides for enhancement of neurogenesis and associated behavioral improvement

Background: Levels of neurotrophic factors and the dentate gyrus neurogenesis are dysregulated in AD brain. The anti-dementia drug Cerebrolysin, which contains several neurotrophic activities, enhances the dentate gyrus neurogenesis and improves cognition in adult rats. To assess the neurogenic/neurotrophic (ngc/ntc) activities and corresponding neurobehavioral effect in mice of 4-11 mer synthetic peptides corresponding to the active regions of CNTF and the possible molecular mechanisms of action of these peptides. Methods: An 11-mer peptide, Peptide 6, and several 4-mer peptides of Peptide 6 were designed based on a biologically active region of CNTF. These peptides were administered to female retired breeders (C57 BL6 mice) either subcutaneously as a slow release bolus or daily IP injections at a dose of 5 to 50 nmoles peptide/day for 4-5 weeks. On days 2-6 of the treatment with the test peptide, the animals received IP 100 mg BrdU/kg/day. Results: Administration of Peptide 6 subcutaneously as a slow release bolus at a dose of 5 nmoles/day for 4 weeks enhanced the dentate gyrus neurogenesis and hippocampal-dependent spatial memory in normal adult mice. This peptide increased proliferation/survival of newborn neurons, along with a general neurotrophic effect. Of the four 4-mer peptides (Peptides 6A, 6B, 6C, and 6D), Peptide 6C was found to enhance most the dentate gyrus neurogenesis in mice. Both Peptide 6 and Peptide 6C increased the expression levels of MAP2 and synaptophysin in the dentate gyrus, and improved cognition in Morris water maze. These peptides had plasma half-lives of over 6 hours and were blood brain permeable. Peptide 6 was found to inhibit LIF-induced haptoglobin secretion from HepG2 cells. Thus, Peptide 6 appears to enhance neurogenesis in adult mice as a competitive inhibitor to LIF which is known to decrease overall neurogenesis in the subventricular zone. Conclusions: Peptide 6 and its neurogenic/neurotrophic fragments are promising candidate drugs for enhancing cognition through increase in ntg/ntc activity in AD and other learning and memory disorders as well as for promoting general cognitive health.

(Supported in part by the NYS Office of Mental Retardation and Developmental Disabilities and a research grant from EBEWE Pharma, Unterach, Austria.)