From synapse to nucleus: Novel targets for treating depression

Covington, Herbert E.; Vialou, Vincent; Nestler, Eric J.

doi:10.1016/j.neuropharm.2009.12.004

Cited by 87 publications

(55 citation statements)

References 159 publications

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“…In R animals, the decrease in hippocampal BDNF concentrations associated with hippocampal morphological changes is consistent with the depressive phenotype described in humans (Sheline et al, 1999;Bremner et al, 2000;Duman and Monteggia, 2006;Pittenger and Duman, 2008). Animal models of depression and psychosocial stress are associated with reduced hippocampal neurogenesis, hippocampal dendritic arborization, and hippocampal BDNF that are prevented by antidepressant treatment (Watanabe et al, 1992;Magariños et al, 1996Magariños et al, , 2011Sapolsky, 2000;Czeh et al, 2001;Buwalda et al, 2005;Yap et al, 2006;Castrén et al, 2007;Czeh and Lucassen, 2007;Becker et al, 2008;Krishnan and Nestler, 2008;Alleva and Francia, 2009;Covington et al, 2009). Depending on studies, the hippocampal spine density is or not affected by stress events (Chen et al, 2010;Magariños et al, 2011).…”

Section: Discussionsupporting

confidence: 59%

Vulnerability to Depression: From Brain Neuroplasticity to Identification of Biomarkers

Blugeot¹,

Rivat²,

Bouvier³

et al. 2011

J. Neurosci.

161

147

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A stressful event increases the risk of developing depression later in life, but the possible predisposing factors remain unknown. Our study aims to characterize latent vulnerability traits underlying the development of depressive disorders in adult animals. Four weeks after a priming stressful event, serum corticosterone concentration returned to control values in all animals, whereas the other biological parameters returned to basal level in only 58% of animals (called nonvulnerable). In contrast, 42% of animals displayed persistent decreased serum and hippocampus BDNF concentrations, reduced hippocampal volume and neurogenesis, CA3 dendritic retraction and decrease in spine density, as well as amygdala neuron hypertrophy, constituting latent vulnerability traits to depression. In this group, called vulnerable, a subsequent mild stress evoked a rise of serum corticosterone levels and a "depressive" phenotype, in contrast to nonvulnerable animals. Intracerebroventricular administration of 7,8-dihydroxyflavone, a selective TrkB receptor agonist, dampened the development of the "depressive" phenotype. Our results thus characterize the presence of latent vulnerability traits that underlie the emergence of depression and identify the association of low BDNF with normal corticosterone serum concentrations as a predictive biomarker of vulnerability to depression.

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Section: Discussionsupporting

confidence: 59%

Vulnerability to Depression: From Brain Neuroplasticity to Identification of Biomarkers

Blugeot¹,

Rivat²,

Bouvier³

et al. 2011

J. Neurosci.

161

147

View full text Add to dashboard Cite

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“…Most of the commonly used antidepressant drugs are biogenic amine inhibitors, some rather specific (e.g., citalopram) and others having multiple actions (e.g., venlafaxine). For some time now, there has been interest in developing therapies for depression based on modulation of glutamatergic tone (Covington et al, 2010;Duman, 2014). In particular, a study published by Zarate et al (2006) showed that subanesthetic doses of ketamine, an inhibitor of NMDA (N-methyl-D-aspartate) type ion channels, has a rapid onset of action as measured by decreased scores on the Hamilton Depression Rating Scale in depressed patients deemed treatment resistant.…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Lindemann

Porter

Scharf

et al. 2015

J Pharmacol Exp Ther

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Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and secondgeneration antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wakepromoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

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“…ERK activity is able to induce phosphorylation of CREB at a specific serine residue, serine133, producing an active transcription complex enabling target gene activation (Conkright et al, 2003), and it is demonstrated that ERK-CREB signal system may play a critical role in the molecular mechanism of depression (Guan et al, 2013). In summary, ERK, CREB and BDNF-mediated signal pathways are indicated to be implicated in the neuroplasticity alterations induced by antidepressants (Covington et al, 2010;Vialou et al, 2013). These previous studies suggest that a CREB-BDNF-ERK circle signal pathway may be involved in the pathogenic mechanism of depression.…”

Section: Discussionmentioning

confidence: 99%

Piper sarmentosum Roxb. produces antidepressant-like effects in rodents, associated with activation of the CREB-BDNF-ERK signaling pathway and reversal of HPA axis hyperactivity

Gao

et al. 2017

Journal of Ethnopharmacology

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Ethnopharmacological relevance: There are many plants of genus Piper which have been reported to induce antidepressant-like effects, Piper sarmentosum (PS) is one of them. PS is a Chinese herbal medicine and a traditional edible vegetable. Materials and Methods:In the present study, the antidepressant-like effects of PS extracts and the ethyl acetate fraction of PS extracts (PSY) were assessed using the open field test (OFT), forced swimming test (FST), and tail suspension test (TST) in mice. Furthermore, we applied a 4 consecutive weeks of chronic unpredictable mild stress (CUMS) as a model of depression in rats, followed by a sucrose preference test. Then we examined the possible mechanisms of this action.The activity of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated by detecting the serum corticosterone (CORT) concentrations, and the protein expression levels of brain-derived neurotrophic factor (BDNF), the phosphorylated form CREB and ERK1/2 were detected by qRT-PCR or Western blot. Results:The results showed that PS extracts (100, 200 mg/kg) and PSY (12.5, 25, 50 mg/kg) treatment produced antidepressant-like effects in mice similar to fluoxetine (20 mg/kg), indicated by the reduced immobility time in the FST and TST, while both had no influence on the locomotor activity in the OFT. PSY treatment significantly increased sucrose preference and reduced serum CORT levels in CUMS rats. Moreover, PSY up-regulated BDNF protein levels, and increased CREB and ERK phosphorylation levels in the hippocampus on CUMS rats. Conclusions:These findings suggest that the antidepressant-like effects of PS extracts and PSY are mediated, at least in part, by modulating HPA axis, BDNF, CREB and ERK phosphorylation and expression in the hippocampus.

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From synapse to nucleus: Novel targets for treating depression

Cited by 87 publications

References 159 publications

Vulnerability to Depression: From Brain Neuroplasticity to Identification of Biomarkers

Vulnerability to Depression: From Brain Neuroplasticity to Identification of Biomarkers

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

Piper sarmentosum Roxb. produces antidepressant-like effects in rodents, associated with activation of the CREB-BDNF-ERK signaling pathway and reversal of HPA axis hyperactivity

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