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      Chronic Treatment with a Phytosomal Preparation Containing Centella asiatica L. and Curcuma longa L. Affects Local Protein Synthesis by Modulating the BDNF-mTOR-S6 Pathway

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          Abstract

          Brain derived neurotrophic factor (Bdnf) is the most diffuse neurotrophin in the central nervous system and it is crucial for the proper brain development and maintenance. Indeed, through the binding to its high affinity receptor TRKB and the activation of different intracellular cascades, it boosts cell survival, neurite growth and spine maturations mechanisms. Here, we evaluated if the chronic oral treatment for 10 days with a phytosomal preparation containing Centella asiatica L. and Curcuma longa L. could improve Bdnf levels in the prefrontal cortex of adult rats. Interestingly we found an increased expression of Bdnf with main effect of the treatment on the mTOR-S6 downstream signaling pathway. Accordingly, we found an increase in the expression of eukaryotic elongation factor (eEF2) with a shift towards the phosphorylated form thus increasing the transcription of Oligophrenin-1, a protein carrying the upstream Open Reading Frame (uORF) which reduction is paralleled by memory dysfunctions. These results show the ability of the phytosome to enhance mTOR-S6 regulated transcription and suggest the possibility to use this preparation in subjects with impairments in neuroplastic mechanisms, memory and cognitive abilities.

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          A neurotrophic model for stress-related mood disorders.

          There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
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            Regulation of translation initiation in eukaryotes: mechanisms and biological targets.

            Translational control in eukaryotic cells is critical for gene regulation during nutrient deprivation and stress, development and differentiation, nervous system function, aging, and disease. We describe recent advances in our understanding of the molecular structures and biochemical functions of the translation initiation machinery and summarize key strategies that mediate general or gene-specific translational control, particularly in mammalian systems.
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              BDNF - a key transducer of antidepressant effects.

              How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an essential determinant of antidepressant efficacy.
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                Author and article information

                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                26 November 2020
                December 2020
                : 8
                : 12
                : 544
                Affiliations
                Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; giulia.sbrini@ 123456unimi.it (G.S.); paola.brivio@ 123456unimi.it (P.B.); enrico.sangiovanni@ 123456unimi.it (E.S.); marco.fumagalli3@ 123456unimi.it (M.F.); giorgio.racagni@ 123456unimi.it (G.R.); mario.dellagli@ 123456unimi.it (M.D.)
                Author notes
                [* ]Correspondence: francesca.calabrese@ 123456unimi.it ; Tel.: +39-02-50318277
                Author information
                https://orcid.org/0000-0003-2811-8628
                https://orcid.org/0000-0001-5378-402X
                https://orcid.org/0000-0001-7946-2424
                Article
                biomedicines-08-00544
                10.3390/biomedicines8120544
                7761389
                33256214
                06cd5640-5101-44b0-bc0b-ec648520e2aa
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 October 2020
                : 24 November 2020
                Categories
                Article

                centella asiatica l.,curcuma longa l.,bdnf,mtor,protein synthesis,neuroplasticity,botanicals

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