ABSTRACT
Title
Acetyl-L-carnitine, a new pharmacological modulator of adult hippocampal neurogenesis in vitro.
Authors
M.M. Valente1,2, V. Bortolotto1,2, P.L. Canonico2, A. Koverech3, M. Grilli1,2.
1Laboratory of Neuroplasticity & Pain, 2DiSCAFF & DFB Center, University of Piemonte Orientale “A. Avogadro”, Novara, Italy, 3Medical Direction, Sigma-Tau, Pomezia, Italy.
1Laboratory of Neuroplasticity & Pain, 2DiSCAFF & DFB Center, University of Piemonte Orientale “A. Avogadro”, Novara, Italy, 3Medical Direction, Sigma-Tau, Pomezia, Italy.
Abstract
Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays a major role as a donor of acetyl groups in several cellular processes of mammalian tissues, including brain. Aside from its major metabolic roles, other functions have been attributed to ALC, including modulation of neurotransmission, release of neurotrophic factors and neurohormones, neuroprotection (Jones LL et al., 2010). Moreover attention has been focused on the pharmacological effects of ALC in neurological disorders, including neuropathic pain and mood disturbances, such as major depression and dysthymia.
Since the proposed role of adult neurogenesis in mood disorders and in the response to antidepressant drugs, we decided to explore the potential activity of ALC as a modulator of adult hippocampal neurogenesis in an in vitro model of adult neural progenitor cells (NPC). In particular, we tested ALC (10 μM-1 mM) activity on the differentiation of adult mouse hippocampal NPC towards the neuronal lineage. Surprisingly ALC increased, in a concentration-dependent manner, the number of mature (MAP-2+/Nestin-) and immature neurons (MAP-2+/Nestin+) derived from adult NPC, with a maximal effect elicited at 1 mM. In parallel, this treatment decreased the number of undifferentiated progenitor cells (MAP-2-/Nestin-). Under the same experimental conditions, we also tested two other carnitines: L-carnitine (LC) and propionyl-L-carnitine (PLC). Interestingly, compared to ALC, PLC appeared to be a less potent activator of NPC neuronal differentiation, while LC had no effect. Moreover we demonstrated that ALC and PLC effects on NPC differentiation were not due to neuroprotective effects on newly generated immature or mature neurons.
Our group has recently proposed a role for NF-κB proteins in regulation of adult hippocampal neurogenesis (Denis-Donini S et al., 2008). Interestingly, acetylation of NF-κB p65 has been shown to mediate, via increased mglu2 gene transcription, ALC analgesic activity (Chiechio S., et al., 2009). In our experimental model the mGlu2/3 agonist, LY379268 (0.1-10 µM) was able to promote NPC differentiation towards the neuronal lineage, similarly to ALC. For these reasons we decided to evaluate the effect of the mGlu2/3 antagonist LY341495 on ALC activity. Pretreatment of adult hippocampal NPC with LY341495 (0.1-10 µM) was able to counteract the proneurogenic activity of ALC, suggesting that it was probably mediated by mGlu2/3 receptors. Furthermore, NF-κB activation lied downstream the signaling pathway mediating ALC proneurogenic effects.
In conclusion, we propose a new pharmacological activity for ALC as a positive modulator of hippocampal neurogenesis in vitro, potentially via mGlu2/3 receptor and NF-κB signaling activation.In the future, we would like to investigate whether this novel activity may contribute to ALC efficacy in relevant animal models of depression and cognitive impairment.
Jones LL et al. (2010). Progress in lipid research. 49: 61-75.
Denis-Donini S et al. (2008). J Neurosci. 28: 3911-3919.
Chiechio S., et al. (2009). TIPS. 31: 153-160.
Since the proposed role of adult neurogenesis in mood disorders and in the response to antidepressant drugs, we decided to explore the potential activity of ALC as a modulator of adult hippocampal neurogenesis in an in vitro model of adult neural progenitor cells (NPC). In particular, we tested ALC (10 μM-1 mM) activity on the differentiation of adult mouse hippocampal NPC towards the neuronal lineage. Surprisingly ALC increased, in a concentration-dependent manner, the number of mature (MAP-2+/Nestin-) and immature neurons (MAP-2+/Nestin+) derived from adult NPC, with a maximal effect elicited at 1 mM. In parallel, this treatment decreased the number of undifferentiated progenitor cells (MAP-2-/Nestin-). Under the same experimental conditions, we also tested two other carnitines: L-carnitine (LC) and propionyl-L-carnitine (PLC). Interestingly, compared to ALC, PLC appeared to be a less potent activator of NPC neuronal differentiation, while LC had no effect. Moreover we demonstrated that ALC and PLC effects on NPC differentiation were not due to neuroprotective effects on newly generated immature or mature neurons.
Our group has recently proposed a role for NF-κB proteins in regulation of adult hippocampal neurogenesis (Denis-Donini S et al., 2008). Interestingly, acetylation of NF-κB p65 has been shown to mediate, via increased mglu2 gene transcription, ALC analgesic activity (Chiechio S., et al., 2009). In our experimental model the mGlu2/3 agonist, LY379268 (0.1-10 µM) was able to promote NPC differentiation towards the neuronal lineage, similarly to ALC. For these reasons we decided to evaluate the effect of the mGlu2/3 antagonist LY341495 on ALC activity. Pretreatment of adult hippocampal NPC with LY341495 (0.1-10 µM) was able to counteract the proneurogenic activity of ALC, suggesting that it was probably mediated by mGlu2/3 receptors. Furthermore, NF-κB activation lied downstream the signaling pathway mediating ALC proneurogenic effects.
In conclusion, we propose a new pharmacological activity for ALC as a positive modulator of hippocampal neurogenesis in vitro, potentially via mGlu2/3 receptor and NF-κB signaling activation.In the future, we would like to investigate whether this novel activity may contribute to ALC efficacy in relevant animal models of depression and cognitive impairment.
Jones LL et al. (2010). Progress in lipid research. 49: 61-75.
Denis-Donini S et al. (2008). J Neurosci. 28: 3911-3919.
Chiechio S., et al. (2009). TIPS. 31: 153-160.