Impact of the neural cell adhesion molecule-derived peptide FGL on seizure progression and cellular alterations in the mouse kindling model.
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.
Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University , Koeniginstrasse 16, D-80539 Munich, Germany.
Christina
C
Zellinger
Josephine D
JD
Salvamoser
Natalie
N
Seeger
Vera
V
Russmann
Heidrun
H
Potschka
D000679:Amygdala / Q000187:drug effects* / Q000503:physiopathology; D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology; D001973:Bromodeoxyuridine; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002491:Central Nervous System Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000089622:Doublecortin Domain Proteins; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D007150:Immunohistochemistry; D058542:Implantable Neurostimulators; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000494:pharmacology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology*
D002491:Central Nervous System Agents; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; C488618:NCAM protein (681-695), human; D019006:Neural Cell Adhesion Molecules; D009479:Neuropeptides; D001973:Bromodeoxyuridine