title: Upregulation of mGlu2 receptors via NF-κB p65 acetylation is involved in the Proneurogenic and antidepressant effects of acetyl-L-carnitine.
abstract: Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF-κB p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect. Here we report that ALC is a proneurogenic molecule, whose effect on neuronal differentiation of adult hippocampal neural progenitors is independent of its neuroprotective activity. The in vitro proneurogenic effects of ALC appear to be mediated by activation of the NF-κB pathway, and in particular by p65 acetylation, and subsequent NF-κB-mediated upregulation of metabotropic glutamate receptor 2 (mGlu2) expression. When tested in vivo, chronic ALC treatment could revert depressive-like behavior caused by unpredictable chronic mild stress, a rodent model of depression with high face validity and predictivity, and its behavioral effect correlated with upregulated expression of mGlu2 receptor in hippocampi of stressed mice. Moreover, chronic, but not acute or subchronic, drug treatment significantly increased adult born neurons in hippocampi of stressed and unstressed mice. We now propose that this mechanism could be potentially involved in the antidepressant effect of ALC in humans. These results are potentially relevant from a clinical perspective, as for its high tolerability profile ALC may be ideally employed in patient subpopulations who are sensitive to the side effects associated with classical antidepressants.
authors.affiliation: 1] Laboratory of Neuroplasticity and Pain, University of Piemonte Orientale "A. Avogadro", Novara, Italy [2] Department of Pharmaceutical Sciences, University of Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Bruna
authors.initials: B
authors.lastname: Cuccurazzu
authors.forename: Valeria
authors.initials: V
authors.lastname: Bortolotto
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Valente
authors.forename: Federica
authors.initials: F
authors.lastname: Ubezio
authors.forename: Aleardo
authors.initials: A
authors.lastname: Koverech
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Grilli
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002755:Choice Behavior / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D018094:Receptors, Metabotropic Glutamate; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C108822:metabotropic glutamate receptor 2; D000108:Acetylcarnitine