TY - JOUR

T1 - Neuroprotective and memory enhancing properties of a dual agonist of the FGF receptor and NCAM

AU - Enevoldsen, Maj N

AU - Kochoyan, Artur

AU - Jurgenson, Monika

AU - Jaako, Külli

AU - Dmytriyeva, Oksana

AU - Walmod, Peter S

AU - Nielsen, Jesper D

AU - Nielsen, Janne

AU - Li, Shizhong

AU - Korshunova, Irina

AU - Klementiev, Boris

AU - Novikova, Tatiana

AU - Zharkovsky, Alexander

AU - Berezin, Vladimir

AU - Bock, Elisabeth

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2012/12

Y1 - 2012/12

N2 - The fibroblast growth factor receptor (FGFR) plays a vital role in the development of the nervous system regulating a multitude of cellular processes. One of the interaction partners of the FGFR is the neural cell adhesion molecule (NCAM), which is known to play an important role in neuronal development, regeneration and synaptic plasticity. Thus, simultaneous activation of FGFR- and NCAM-mediated signaling pathways may be expected to affect processes underlying neurodegenerative diseases. We here report the identification of a peptide compound, Enreptin, capable of interacting with both FGFR and NCAM. We demonstrate that this dual specificity agonist induces phosphorylation of FGFR and differentiation and survival of primary neurons in vitro, and that these effects are inhibited by abrogation of both NCAM and FGFR signaling pathways. Furthermore, Enreptin crosses the blood-brain barrier after subcutaneous administration, enhances long-term memory in normal mice and ameliorates memory deficit in mice with induced brain inflammation. Moreover, Enreptin reduces cognitive impairment and neuronal death induced by Aß25-35 in a rat model of Alzheimer's disease, and reduces the mortality rate and clinical signs of experimental autoimmune encephalomyelitis in rats. Thus, Enreptin is an attractive candidate for the treatment of neurological diseases.

AB - The fibroblast growth factor receptor (FGFR) plays a vital role in the development of the nervous system regulating a multitude of cellular processes. One of the interaction partners of the FGFR is the neural cell adhesion molecule (NCAM), which is known to play an important role in neuronal development, regeneration and synaptic plasticity. Thus, simultaneous activation of FGFR- and NCAM-mediated signaling pathways may be expected to affect processes underlying neurodegenerative diseases. We here report the identification of a peptide compound, Enreptin, capable of interacting with both FGFR and NCAM. We demonstrate that this dual specificity agonist induces phosphorylation of FGFR and differentiation and survival of primary neurons in vitro, and that these effects are inhibited by abrogation of both NCAM and FGFR signaling pathways. Furthermore, Enreptin crosses the blood-brain barrier after subcutaneous administration, enhances long-term memory in normal mice and ameliorates memory deficit in mice with induced brain inflammation. Moreover, Enreptin reduces cognitive impairment and neuronal death induced by Aß25-35 in a rat model of Alzheimer's disease, and reduces the mortality rate and clinical signs of experimental autoimmune encephalomyelitis in rats. Thus, Enreptin is an attractive candidate for the treatment of neurological diseases.

U2 - 10.1016/j.nbd.2012.07.016

DO - 10.1016/j.nbd.2012.07.016

M3 - Journal article

C2 - 22842016

VL - 48

SP - 533

EP - 545

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 3

ER -