Evidence for biological activity of two N-terminal fragments of neurotensin, neurotensin_1-8 and neurotensin_1-10

Intracisternal (i.c.) administration of the endogenous tridecapeptide neurotensin (NT) has been previously shown to significantly reduced the incidence of cold-restraint stress (CRS)-induced gastric ulcers in rats. In this study we confirm the cytoprotective activity of central NT, and document structure-activity relationships for this effect of NT. When tested in a dose equimolar to 17.9 nmol of NT the NT analogs [Gln⁴]NT, d-Trp¹¹-NT, and d-Arg⁸-NT were cytoprotective, whereas d-Arg[⁹-NT was not. Gonadotropin-releasing hormone (Gn-RH) and melanocyte-stimulating hormone-release inhibiting factor (MIF-1), two oligopeptides structurally unrelated to NT exhibited no cytoprotective efficacy in this paradigm. The C-terminal fragments of NT, xenopsin and NT_8-13, and the N-terminal fragment NT_1-6 were completely ineffective. Finally, NT_1-8 and NT_1-10, two N-terminal fragments of NT produced significant cytoprotective activity at this dose level. The cytoprotection afforded by NT_1-8 and NT_1-10, like that of NT, was dose-dependent with ED₅₀'s similar to that of NT (NT = 16.2 nmol, NT_1-8 = 17.8 nmol and NT_1-10 = 19.9 nmol). In conclusion, we demonstrate that smaller molecular weight forms of NT thought to be degradation products of NT can effectively exert biological effects.