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-kB 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-kB pathway, and in particular by p65 acetylation, and subsequent NF-kB-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.

ALCAR Exerts Neuroprotective and Pro-Neurogenic Effects by Inhibition of Glial Activation and Oxidative Stress via Activation of the Wnt/β-Catenin Signaling in Parkinsonian Rats

“…In addition, attenuation of microglial activation also induced the survival of NSC and immature cell population, so it could be partially involved in neuroprotective and proneurogenic effect of ALCAR. Recently, neurogenic potential of ALCAR is also reported in chronic mild stress model in mice, where ALCAR treatment enhanced the newborn neurons in adult hippocampus [52].…”

The Noradrenergic Component in Tapentadol Action Counteractsμ-Opioid Receptor–Mediated Adverse Effects on Adult Neurogenesis

“…As shown in Fig. 1 (Cuccurazzu et al, 2013). To characterize the effects of drugs acting on neuronal differentiation of hippocampal NPCs, we performed immunolabeling experiments with antibodies against the neuronal marker MAP-2.…”

60 YEARS OF NEUROENDOCRINOLOGY: Redefining neuroendocrinology: stress, sex and cognitive and emotional regulation

“…One novel agent is acetyl-L-carnitine (LAC) that decreases depressive-like behavior within 3 days of treatment in a stress-induced and a genetic model of depression-like behavior while SSRI’s and tricyclic drugs have no effect in that time frame (Nasca et al 2013). Antidepressant effects of LAC have been shown in other animal models that mimic features of the spectrum of depressive disorders in humans (Cuccurazzu et al 2013) and need to be expanded to human treatment resistant depression (Flight 2013, Russo & Charney 2013). The rapid antidepressant action of LAC is mediated by acetylation of the histone H3K27 bound to the promoter gene of the metabotropic glutamate receptor, mGlu2, which inhibits glutamate release to the synapse.…”