Impact of the Neural Cell Adhesion Molecule-Derived Peptide FGL on Seizure Progression and Cellular Alterations in the Mouse Kindling Model

Abstract

The neural cell adhesion molecule peptide mimetic fibroblast growth loop (FGL) proved to exert neuroprotective, neurotrophic, and anti-inflammatory effects in different in vitro and in vivo experiments. Based on this beneficial efficacy profile, it is currently in clinical development for neurodegenerative diseases and brain insults. Here, we addressed the hypothesis that the peptide might affect development of seizures in a kindling paradigm, as well as associated behavioral and cellular alterations. Both doses tested, 2 and 10 mg/kg FGL, significantly reduced the number of stimulations necessary to induce a generalized seizure. FGL did not exert relevant effects on the behavioral patterns of kindled animals. As expected, kindling increased the hippocampal cell proliferation rate. Whereas the low dose of FGL did not affect this kindling-associated alteration, 10 mg/kg FGL proved to attenuate the expansion of the doublecortin-positive cell population. These data suggest that FGL administration might have an impact on disease-associated alterations in the hippocampal neuronal progenitor cell population. In conclusion, the effects of the peptide mimetic FGL in the kindling model do not confirm a disease-modifying effect with a beneficial impact on the development or course of epilepsy. The results obtained with FGL rather raise some concern regarding a putative effect, which might promote the formation of a hyperexcitable network. Future studies are required to further assess the risks in models with development of spontaneous seizures.

Peptides as Therapeutic Agents for Inflammatory-Related Diseases

“…The CD200 expression on neuronal cells is regulated by the anti-inflammatory cytokine IL-4, in fact, IL-4 -/- mice display reduced CD200 expression, which increases when they are treated with exogenous IL-4 [ 86 , 87 ]. Recent studies have demonstrated that a peptide called FGL (fibroblast growth loop) is able to modulate the hippocampus inflammation, to regulate the activation of microglial cells both in vivo and in vitro [ 23 ]. FGL is a 15 mer fragment of neural cell adhesion molecule (NCAM) protein spanning residues Glu 681 –Ala 695 ; it is involved in the interaction between NCAM and fibroblast growth factor receptor (FGFR).…”