Rapid-acting antidepressant-like effects of acetyl-l-carnitine mediated by PI3K/AKT/BDNF/VGF signaling pathway in mice

Wang, W.; Yang, Lu; Xue, Zhancheng; Li, C.; Wang, C.; Zhao, Xin; Zhang, J.; Wei, Xiaofei; Chen, X.; Cui, Wei; Wang, Q.; Zhou, Wenhua

doi:10.1016/j.neuroscience.2014.11.025

Cited by 63 publications

(48 citation statements)

References 54 publications

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“…Importantly, LAC levels are markedly reduced in patients with major depressive disorder, particularly in those with treatment-resistant depression (40). Our results in the forced swim test are in line with previous rodent studies showing the ability of LAC to reduce immobility time in this test (23–25, 41) with several small clinical trials in humans reporting effectiveness of LAC treatment in patients with depressive disorders and related conditions (29, 43, 45–48; for systematic review and meta-analysis see Veronese et al, 2018). Strikingly, LAC supplementation did not change behavioral responses in subordinate/resilient mice that were not affected by CRS, an observation well aligned with findings in the literature indicating lack of LAC effects in non-depressed individuals.…”

Section: Discussionsupporting

confidence: 90%

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo¹H-magnetic resonance spectroscopy study at 14 T

Cherix

Larrieu²,

Grosse

et al. 2019

Preprint

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BackgroundEmerging evidence suggests that hierarchical status may provide vulnerability to develop stress-induced depression. Energy metabolism in the nucleus accumbens (NAc) was recently related to hierarchical status and vulnerability to develop depression-like behavior. Acetyl-L-carnitine (LAC), a mitochondria-boosting supplement, has shown promising antidepressant-like effects opening promising therapeutic strategies for restoring energy balance in depressed patients. Here, we investigated the metabolic impact in the NAc of antidepressant LAC treatment in chronically stressed mice.MethodMice were characterized for emotional behaviors and social rank. They were then exposed to chronic restraint stress (CRS) for 21 days and subsequently tested in a social behavior (SB) test. A group of mice was also given LAC supplementation during the 7 last CRS days. Mice were then tested in the SB and forced swim tests (FST) and scanned in vivo using 1H-magnetic resonance spectroscopy (1H-MRS) to quantitatively assess the NAc neurochemical profile.ResultsDominant, but not subordinate, mice showed behavioral vulnerability to CRS. In the NAc, dominant mice showed reduced levels of several energy-related metabolites. LAC treatment counteracted stress-induced behavioral changes in dominant mice, and normalized levels of taurine, phosphocreatine, glutamine and phosphocholine in the NAc. No major accumbal metabolic changes were observed in subordinate mice.ConclusionHigh social rank is confirmed as a vulnerability factor to develop chronic stress-induced depressive-like behaviors. We reveal a metabolic signature in the NAc for the antidepressant-like effects of LAC in vulnerable mice, characterized by restoration of stress-induced alterations in neuroenergetics and lipid function.

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Section: Discussionsupporting

confidence: 90%

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo¹H-magnetic resonance spectroscopy study at 14 T

Cherix

Larrieu²,

Grosse

et al. 2019

Preprint

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“…Thus, as an approach to promote resilience to stress, we found that three days of oral administration with acetyl-L-carnitine (LAC) - a novel antidepressant that was shown to be more rapidly effective than fluoxetine and chlorimipramine in humans and animal models 19-21, 35, 36 – enhances behaviors impaired by 21 days CRS and promotes structural plasticity of a key limbic brain region, the medial amygdala, that is in a direction opposite to the effects of CRS.…”

Section: Discussionmentioning

confidence: 99%

Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant

et al. 2016

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The adult brain is capable of adapting to internal and external stressors by undergoing structural plasticity, and failure to be resilient and preserve normal structure and function is likely to contribute to depression and anxiety disorders. While the hippocampus has provided the gateway for understanding stress effects on the brain, less is known about the amygdala, a key brain area involved in the neural circuitry of fear and anxiety. Here, in mice more vulnerable to stressors, we demonstrate structural plasticity within the medial and basolateral regions of the amygdala in response to prolonged 21day chronic restraint stress (CRS). Three days before the end of CRS, treatment with the putative, rapidly acting antidepressant, acetyl-L-carnitine (LAC) in the drinking water opposed the direction of these changes. Behaviorally, the LAC treatment during the last part of CRS enhanced resilience, opposing the effects of CRS, as shown by an increased social interaction and reduced passive behavior in a forced swim test. Furthermore, CRS mice treated with LAC show resilience of the CRS-induced structural remodeling of medial amygdala (MeA) stellate neurons. Within the basolateral (BLA) amygdala, LAC did not reduce, but slightly enhanced, the CRS-increased length and number of intersections of pyramidal neurons. No structural changes were observed in MeA bipolar neurons, BLA stellate neurons, or in lateral amygdala (LA) stellate neurons. Our findings identify MeA stellate neurons as an important component in the responses to stress and LAC action and show that LAC can promote structural plasticity of the MeA. This may be useful as a model for increasing resilience to stressors in at risk populations.

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“…A number of studies have confirmed that BDNF expression promoted the survival of neurons and upregulated the release of neurotransmitters by combining with tropomyosin-related kinase B (TrkB) and subsequently activating the phosphatidylinositol 3-kinase (PI3K)/Akt (also known as protein kinase B) signaling pathway, which served a significant role in neural protection (14)(15)(16). In addition, VEGF was revealed to regulate the PI3K/Akt signaling to inhibit the activity of Caspase-3 and to regulate voltage-gated potassium channels, thereby, reducing ischemia-induced neuronal death.…”

Section: Introductionmentioning

confidence: 99%

Effects of dexmedetomidine post‑treatment on BDNF and VEGF expression following cerebral ischemia/reperfusion injury in rats

Jia

Wang

et al. 2018

Mol Med Report

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Brain‑derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) serves a significant role in neural protection by activating the phosphatidylinositol 3‑kinase (PI3K)/Akt signaling pathway, which also was associated with the neuroprotective the treatment with dexmedetomidine (DEX). The present study aimed to further explore whether treatment with DEX post‑IR increased the expression level of BDNF and VEGF in the rat brain. A total of 30 healthy, clean male Wistar rats were randomly divided into 3 experimental groups: Control group, ischemia/reperfusion (I/R) group and DEX treatment group. Subsequently, BDNF and VEGF mRNA and protein expression levels were analyzed. The results indicated that the mRNA expression levels of BDNF and VEGF were higher in the I/R and DEX groups compared with expression levels in the Control group at 6 h and 1 day post‑treatment; the levels of BNDF mRNA expression were higher in the DEX group compared with the I/R group. The levels of BDNF and VEGF protein expression in the I/R and DEX groups were also significantly higher compared with those in the Control group. I/R surgery significantly increased the expression of BDNF and VEGF protein DEX group at 6 h, day 1 and day 3 compared with expression levels in the I/R group. Results from the present study indicated that post‑surgical treatment with DEX may increase the expression of BDNF and VEGF following I/R, which may serve a role in nerve protection.

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Rapid-acting antidepressant-like effects of acetyl-l-carnitine mediated by PI3K/AKT/BDNF/VGF signaling pathway in mice

Cited by 63 publications

References 54 publications

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo¹H-magnetic resonance spectroscopy study at 14 T

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo¹H-magnetic resonance spectroscopy study at 14 T

Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant

Effects of dexmedetomidine post‑treatment on BDNF and VEGF expression following cerebral ischemia/reperfusion injury in rats

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Rapid-acting antidepressant-like effects of acetyl-l-carnitine mediated by PI3K/AKT/BDNF/VGF signaling pathway in mice

Cited by 63 publications

References 54 publications

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo1H-magnetic resonance spectroscopy study at 14 T

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo1H-magnetic resonance spectroscopy study at 14 T

Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant

Effects of dexmedetomidine post‑treatment on BDNF and VEGF expression following cerebral ischemia/reperfusion injury in rats

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Resources

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Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo¹H-magnetic resonance spectroscopy study at 14 T

Metabolic signature in nucleus accumbens for anti-depressant-like effects of acetyl-L-carnitine: Anin vivo¹H-magnetic resonance spectroscopy study at 14 T