RESUMO
Hexafins are recently identified low-molecular-weight peptide agonists of the fibroblast growth factor receptor (FGFR), derived from the beta6-beta7 loop region of various FGFs. Synthetic hexafin peptides have been shown to bind to and induce tyrosine phosphorylation of FGFR1, stimulate neurite outgrowth, and promote neuronal survival in vitro. Thus, the pronounced biological activities of hexafins in vitro make them attractive compounds for pharmacological studies in vivo. The present study investigated the effects of subcutaneous administration of hexafin1 and hexafin2 (peptides derived from FGF1 and FGF2, respectively) on social memory, exploratory activity, and anxiety-like behavior in adult rats. Treatment with hexafin1 and hexafin2 resulted in prolonged retention of social memory. Furthermore, rats treated with hexafin2 exhibited decreased anxiety-like behavior in the elevated plus maze. Employing an R6/2 mouse model of Huntington's disease (HD), we found that although hexafin2 did not affect the progression of motor symptoms, it alleviated deficits in activity related to social behavior, including sociability and social novelty. Thus, hexafin2 may have therapeutic potential for the treatment of HD.
Assuntos
Comportamento Animal/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/agonistas , Peptídeos/agonistas , Peptídeos/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/agonistas , Animais , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Fator 1 de Crescimento de Fibroblastos/síntese química , Fator 1 de Crescimento de Fibroblastos/farmacologia , Fator 2 de Crescimento de Fibroblastos/síntese química , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fatores de Crescimento de Fibroblastos/fisiologia , Humanos , Injeções Subcutâneas/métodos , Masculino , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacologia , Peptídeos/síntese química , Ratos , Ratos Sprague-Dawley , Receptores de Fatores de Crescimento de Fibroblastos/fisiologiaRESUMO
Fibroblast growth factors (FGFs) constitute a family of at least 23 structurally related heparin-binding proteins that are involved in regulation of cell growth, survival, differentiation and migration. Sucrose octasulfate (SOS), a chemical analogue of heparin, has been demonstrated to activate FGF signalling pathways. The structure of rat FGF1 crystallized in the presence of SOS has been determined at 2.2 A resolution. SOS-mediated dimerization of FGF1 was observed, which was further supported by gel-filtration experiments. The major contributors to the sulfate-binding sites in rat FGF1 are Lys113, Lys118, Arg122 and Lys128. An arginine at position 116 is a consensus residue in mammalian FGF molecules; however, it is a serine in rat FGF1. This difference may be important for SOS-mediated FGF1 dimerization in rat.
Assuntos
Antiulcerosos/química , Fator 1 de Crescimento de Fibroblastos/química , Sacarose/análogos & derivados , Animais , Sítios de Ligação , Cromatografia em Gel , Cristalografia por Raios X , DNA Complementar , Dimerização , Escherichia coli/genética , Fator 1 de Crescimento de Fibroblastos/síntese química , Fator 1 de Crescimento de Fibroblastos/metabolismo , Ligação de Hidrogênio , Modelos Moleculares , Peso Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Sacarose/química , Sacarose/metabolismoRESUMO
Linear synthetic peptides related to the human Fibroblast Growth Factor-1 (hFGF-1) segment [112-147] were tested for their capacity of mimicking FGF mitogenic activity, binding to heparin-Sepharose columns, stimulating DNA synthesis and competing with hFGF-1 for the cellular receptors. The results obtained indicated that the activity of these compounds is dependent on the presence of the sequence WFVGLK in their structures. The affinity for the cellular receptors increased when this sequence was elongated in order to incorporate amino acid residues that are important for FGF-heparin binding.
