Modulatory Effects of Cortexin and Cortagen on Locomotor Activity and Anxiety-Related Behavior in Mice

Abstract

Objective: Cortexin is a polypeptide extract, used in clinics for its effects on memory, attention, and brain cortical processes. A synthetic analog of one Cortexin fraction, Cortagen (i.e. Ala-Glu-Asp-Pro peptide), was developed. Both agents stimulate neural growth in vitro, presumably in association with neurotrophic factors. We assessed the psychoactive effects of Cortexin and cortagen, using elevated plus maze (EPM) and locomotor activity habituation (LAH) paradigms in CD-1 mice. In Exp. I, mice were injected with Cortexin (0, 0.25, 0.50, or 1.00 mg/kg i.p.) and tested in the EPM (acute) and the LAH (sub-chronic response). In Exp. II, separate mice were injected with cortagen (0, 0.01, 0.03, or 0.10 mg/kg i.p.) or a reference dose of Cortexin, and tested in the LAH (acute and sub-chronic) and the EPM (sub-chronic response). Results: Evidence of anxyolitic effects was found in the EPM for acute Cortexin treatment at the 0.25 and 1.00 mg/kg dosages. The Cortexin 0.25 mg/kg was selected as reference dose for Exp. II, since it had no locomotor effects over 4 days, whilst the 1.00 mg/kg dose led to the development of hyperactivity. When comparing to Cortexin reference, the 0.03 mg/kg dose of cortagen enhanced locomotion both upon acute and after sub-chronic treatment, also having few effects on anxiety-related behavior. Conversely, following a sub-chronic regimen (5 days), the Cortexin reference and the other doses of cortagen turned out to produce anxiogenic effects. Conclusion: Cortexin has anxiolytic-like effects when given acutely, and anxiogenic-like arousal emerges following repeated treatment. Conversely, acute and sub-chronic cortagen leads to motor stimulation with no side effects on emotional-affective profiles. Such behavioral stimulation may find beneficial employment in the treatment of affective / depressive symptoms in humans. Peptides are active in very low dosages with no side effects, and deserve deeper investigation for their promising role in therapy.