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P.4.003 A neural cell adhesion molecule (NCAM)-derived peptide, FGL, counteracts serotonergic dysfunction in NCAM-deficient mice
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Depression: towards new drug targets
P.4.003 A neural cell adhesion molecule (NCAM)derived peptide, FGL, counteracts serotonergic dysfunction in NCAMdeficient mice A. Aonurm-Helm1 ° , K. Anier1 , V. Berezin2 , E. Bock2 , A. Zharkovsky1 . 1 University of Tartu, Department of Pharmacology, Tartu, Estonia; 2 University of Copenhagen, Department of Neuroscience and Pharmacology, Copenhagen, Denmark For many years the main hypothesis of the development of depression has been the monoaminergic theory. Numerous reports link the mechanisms of mood disorders in particular with dysfunction of the serotonergic system. Recently it has also been suggested that mood disorders are induced by reduced brain plasticity. The main promoter of brain plasticity in the CNS is the neural cell adhesion molecule (NCAM) which belongs to the immunoglobulin superfamily of adhesion molecules and can regulate brain plasticity by its interaction with the fibroblast growth factor (FGF) receptor [1]. It has been suggested that dysregulated NCAM-mediated signaling is implicated in the pathogenesis of mood disorders. A 15 amino acid long peptide, named FGL, has been developed, and it has been shown to bind and activate the FGF receptor. In vivo, after systemic administration, the FGL peptide was found to enhance cognitive behavior, and to ameliorate the signs of depression in NCAM-deficient mice [2,3]. The aim of the present study was to explore whether NCAM knockout mice have a dysfunction of the serotonergic system and whether the FGL peptide can ameliorate alterations observed in these animals. Heterozygotic NCAM+/− mice were purchased from Jackson Laboratories (US). F2 generation NCAM−/− mice and their wild-type littermates with an average weight of 26.0 g were used in this study at the age of 3−5 months. For pharmacological studies NCAM-knockout mice and their wild-type littermates were divided into two sub-groups of 10 animals in each. Either vehicle or FGL peptide solutions were administered s.c. once a day for 14 consecutive days. For a positive control, amitriptyline in the dose of 10 mg/kg was used in an additional group of animals (n = 10). Adult NCAM knockout mice demonstrated reduced expression of the serotonin transporter (SERT) and reduced expression of tryptophan hydroxylase (TPH). This was accompanied by reduced tissue levels of serotonin and its major metabolite 5-hydroxyindole acetic acid, and reduced density of serotonergic fibers in both the frontal cortex and hippocampus. The observed changes in the serotonergic system seem to develop during prenatal period, since already newborn NCAM knockout mice had
a reduced SERT protein level. Repeated administration of the FGL peptide, known to mimic NCAM interactions with the FGF receptor, restored the expression of SERT, increased the levels of tryptophan hydroxylase protein, and restored serotonergic innervation of the frontal cortex and hippocampus in the adult NCAM knockout mice. We propose that the observed changes in the serotoninergic system in NCAM knockout mice are related to the depression-like phenotype recently described in these animals. Furthermore, the ability of FGL peptide to restore activity of serotonergic system explains the antidepressant-like activity of this molecule. These data open new avenue for the search of new peptide molecules which mimic actions of NCAM for the treatment of depression. Reference(s) [1] Walmod, P.S., Kolkova, K., Berezin, V., Bock, E., 2004 Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem Res 29, 2015–2035. [2] Klementiev, B., Novikova, T., Novitskaya, V., Walmod, P.S., Dmytriyeva, O., Pakkenberg, B., Berezin, V., Bock, E., 2007 A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25−35. Neuroscience 145, 209–224. [3] Aonurm-Helm, A., Jurgenson, M., Zharkovsky, T., Sonn, K., Berezin, V., Bock, E., Zharkovsky, A., 2008 Depression-like behaviour in neural cell adhesion molecule (NCAM)-deficient mice and its reversal by an NCAM-derived peptide, FGL. Eur J Neurosci 28, 1618–1628. P.4.004 P-glycoprotein inhibition enhances transport of the antidepressant imipramine across the blood–brain barrier F.E. O’Brien1 ° , G. Clarke2 , P. Fitzgerald3 , T.G. Dinan2 , B.T. Griffin4 , J.F. Cryan5 . 1 University College Cork, Alimentary Pharmabiotic Centre/School of Pharmacy, Cork City, Ireland; 2 University College Cork, Alimentary Pharmabiotic Centre/Department of Psychiatry, Cork City, Ireland; 3 University College Cork, Alimentary Pharmabiotic Centre, Cork City, Ireland; 4 University College Cork, School of Pharmacy, Cork City, Ireland; 5 University College Cork, Alimentary Pharmabiotic Centre/Department of Anatomy & Neuroscience, Cork City, Ireland Purpose: Recent studies indicate that P-glycoprotein (P-gp) efflux at the blood–brain barrier (BBB) may
Depression: towards new drug targets
P.4.003 A neural cell adhesion molecule (NCAM)derived peptide, FGL, counteracts serotonergic dysfunction in NCAMdeficient mice A. Aonurm-Helm1 ° , K. Anier1 , V. Berezin2 , E. Bock2 , A. Zharkovsky1 . 1 University of Tartu, Department of Pharmacology, Tartu, Estonia; 2 University of Copenhagen, Department of Neuroscience and Pharmacology, Copenhagen, Denmark For many years the main hypothesis of the development of depression has been the monoaminergic theory. Numerous reports link the mechanisms of mood disorders in particular with dysfunction of the serotonergic system. Recently it has also been suggested that mood disorders are induced by reduced brain plasticity. The main promoter of brain plasticity in the CNS is the neural cell adhesion molecule (NCAM) which belongs to the immunoglobulin superfamily of adhesion molecules and can regulate brain plasticity by its interaction with the fibroblast growth factor (FGF) receptor [1]. It has been suggested that dysregulated NCAM-mediated signaling is implicated in the pathogenesis of mood disorders. A 15 amino acid long peptide, named FGL, has been developed, and it has been shown to bind and activate the FGF receptor. In vivo, after systemic administration, the FGL peptide was found to enhance cognitive behavior, and to ameliorate the signs of depression in NCAM-deficient mice [2,3]. The aim of the present study was to explore whether NCAM knockout mice have a dysfunction of the serotonergic system and whether the FGL peptide can ameliorate alterations observed in these animals. Heterozygotic NCAM+/− mice were purchased from Jackson Laboratories (US). F2 generation NCAM−/− mice and their wild-type littermates with an average weight of 26.0 g were used in this study at the age of 3−5 months. For pharmacological studies NCAM-knockout mice and their wild-type littermates were divided into two sub-groups of 10 animals in each. Either vehicle or FGL peptide solutions were administered s.c. once a day for 14 consecutive days. For a positive control, amitriptyline in the dose of 10 mg/kg was used in an additional group of animals (n = 10). Adult NCAM knockout mice demonstrated reduced expression of the serotonin transporter (SERT) and reduced expression of tryptophan hydroxylase (TPH). This was accompanied by reduced tissue levels of serotonin and its major metabolite 5-hydroxyindole acetic acid, and reduced density of serotonergic fibers in both the frontal cortex and hippocampus. The observed changes in the serotonergic system seem to develop during prenatal period, since already newborn NCAM knockout mice had
a reduced SERT protein level. Repeated administration of the FGL peptide, known to mimic NCAM interactions with the FGF receptor, restored the expression of SERT, increased the levels of tryptophan hydroxylase protein, and restored serotonergic innervation of the frontal cortex and hippocampus in the adult NCAM knockout mice. We propose that the observed changes in the serotoninergic system in NCAM knockout mice are related to the depression-like phenotype recently described in these animals. Furthermore, the ability of FGL peptide to restore activity of serotonergic system explains the antidepressant-like activity of this molecule. These data open new avenue for the search of new peptide molecules which mimic actions of NCAM for the treatment of depression. Reference(s) [1] Walmod, P.S., Kolkova, K., Berezin, V., Bock, E., 2004 Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem Res 29, 2015–2035. [2] Klementiev, B., Novikova, T., Novitskaya, V., Walmod, P.S., Dmytriyeva, O., Pakkenberg, B., Berezin, V., Bock, E., 2007 A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25−35. Neuroscience 145, 209–224. [3] Aonurm-Helm, A., Jurgenson, M., Zharkovsky, T., Sonn, K., Berezin, V., Bock, E., Zharkovsky, A., 2008 Depression-like behaviour in neural cell adhesion molecule (NCAM)-deficient mice and its reversal by an NCAM-derived peptide, FGL. Eur J Neurosci 28, 1618–1628. P.4.004 P-glycoprotein inhibition enhances transport of the antidepressant imipramine across the blood–brain barrier F.E. O’Brien1 ° , G. Clarke2 , P. Fitzgerald3 , T.G. Dinan2 , B.T. Griffin4 , J.F. Cryan5 . 1 University College Cork, Alimentary Pharmabiotic Centre/School of Pharmacy, Cork City, Ireland; 2 University College Cork, Alimentary Pharmabiotic Centre/Department of Psychiatry, Cork City, Ireland; 3 University College Cork, Alimentary Pharmabiotic Centre, Cork City, Ireland; 4 University College Cork, School of Pharmacy, Cork City, Ireland; 5 University College Cork, Alimentary Pharmabiotic Centre/Department of Anatomy & Neuroscience, Cork City, Ireland Purpose: Recent studies indicate that P-glycoprotein (P-gp) efflux at the blood–brain barrier (BBB) may