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Enzymatic Depletion of the Polysialic Acid Moiety Associated with the Neural Cell Adhesion Molecule Inhibits Antidepressant Efficacy.
- Source :
-
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology [Neuropsychopharmacology] 2016 May; Vol. 41 (6), pp. 1670-80. Date of Electronic Publication: 2015 Nov 04. - Publication Year :
- 2016
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Abstract
- Antidepressant drugs are too often ineffective, the exact mechanism of efficacy is still ambiguous, and there has been a paucity of novel targets for pharmacotherapy. In an attempt to understand the pathogenesis of depression and subsequently develop more efficacious antidepressant drugs, multiple theories have been proposed, including the modulation of neurotransmission, the upregulation of neurogenesis and neurotrophic factors, normalizing hypothalamic-pituitary-adrenal reactivity, and the reduction of neuroinflammation; all of which have supporting lines of evidence. Therefore, an ideal molecular target for novel pharmaceutical intervention would function at the confluence of these theories. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) functions broadly, serving to mediate synaptic plasticity, neurogenesis, neurotrophic factor signaling, and inflammatory signaling throughout the brain; all of which are associated with the pathophysiology and treatment of depression. Moreover, the expression of PSA-NCAM is reduced by depression, and conversely enhanced by antidepressant treatment, particularly within the hippocampus. Here we demonstrate that selectively cleaving the polysialic acid moiety, using the bacteriophage-derived enzyme endoneuraminidase N, completely inhibits the antidepressant efficacy of the selective-serotonin reuptake inhibitor fluoxetine (FLX) in a chronic unpredictable stress model of depression. We also observe a corresponding attenuation of FLX-induced hippocampal neuroplasticity, including decreased hippocampal neurogenesis, synaptic density, and neural activation. These data indicate that PSA-NCAM-mediated neuroplasticity is necessary for antidepressant action; therefore PSA-NCAM represents an interesting, and novel, target for pharmacotherapy.
- Subjects :
- Animals
Corticosterone blood
Depression drug therapy
Disease Models, Animal
Glycoside Hydrolases metabolism
Hippocampus drug effects
Hippocampus metabolism
Male
Neural Cell Adhesion Molecule L1 deficiency
Neural Cell Adhesion Molecule L1 metabolism
Neuronal Plasticity drug effects
Rats
Rats, Sprague-Dawley
Sialic Acids deficiency
Sialic Acids metabolism
Testosterone blood
Treatment Outcome
Antidepressive Agents, Second-Generation pharmacology
Fluoxetine pharmacology
Neural Cell Adhesion Molecule L1 physiology
Sialic Acids physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1740-634X
- Volume :
- 41
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 26530284
- Full Text :
- https://doi.org/10.1038/npp.2015.337