Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents

Abstract(R,S)-ketamine elicits rapid-acting and sustained antidepressant actions in treatment-resistant patients with depression. (R)-ketamine produces longer-lasting antidepressant effects than (S)-ketamine in rodents; however, the precise molecular mechanisms underlying antidepressant actions of (R)-ketamine remain unknown. Using isobaric Tag for Relative and Absolute Quantification, we identified nuclear receptor-binding protein 1 (NRBP1) that could contribute to different antidepressant-like effects of the two enantiomers in chronic social defeat stress (CSDS) model. NRBP1 was localized in the microglia and neuron, not astrocyte, of mouse medial prefrontal cortex (mPFC). (R)-ketamine increased the expression of NRBP1, brain-derived neurotrophic factor (BDNF), and phosphorylated cAMP response element binding protein (p-CREB)/CREB ratio in primary microglia cultures thorough the extracellular signal-regulated kinase (ERK) activation. Furthermore, (R)-ketamine could activate BDNF transcription through activation of CREB as well as MeCP2 (methyl-CpG binding protein 2) suppression in microglia. Single intracerebroventricular (i.c.v.) injection of CREB-DNA/RNA heteroduplex oligonucleotides (CREB-HDO) or BDNF exon IV-HDO blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Moreover, microglial depletion by colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. In addition, inhibition of microglia by single i.c.v. injection of mannosylated clodronate liposomes (MCLs) significantly blocked the antidepressant-like effects of (R)-ketamine in CSDS susceptible mice. Finally, single i.c.v. injection of CREB-HDO, BDNF exon IV-HDO or MCLs blocked the beneficial effects of (R)-ketamine on the reduced dendritic spine density in the mPFC of CSDS susceptible mice. These data suggest a novel ERK-NRBP1-CREB-BDNF pathways in microglia underlying antidepressant-like effects of (R)-ketamine.

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“…CSDS was performed according to the previous reports [ 49 – 53 ] (for details, see Supplementary Information ).…”

Section: Methodsmentioning

confidence: 99%

Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine

et al. 2021

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“…Alpha-7 nAChR is a cholinergic receptor. It is known that this receptor regulates the ascending cholinergic inflammatory pathway, in which there is a decrease in inflammation through the vagus nerve with decreased activity of peripheral macrophages ( Yaoyu et al, 2021 ).…”

Section: Inflammatory Response and Immune System Associated With Mddmentioning

confidence: 99%

Inflammatory Process and Immune System in Major Depressive Disorder

Ruiz

Ángel

Brizuela

et al. 2021

International Journal of Neuropsychopharmacology

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Major depressive disorder (MDD) is one of the most common psychiatric illnesses in the general population. In mental disorders, the activation of inflammatory pathways in the brain is a major producer of excitotoxicity and an inducer of oxidative stress. The occurrence of these 2 events is partly responsible for the neuronal damage inherent in patients with mental disorders. In the case of MDD, the release of hormone and increase in pro-inflammatory cytokines in plasma and indicators of oxidative stress have been identified as consequences of this event. The most important affectations in patients with MDD are changes in their cognitive and executive functions due to brain inflammation. Hence, these biomarkers can serve as diagnostic and severity classification tools and treatment. In this work, we described the communication pathway between the immune and neuroendocrine systems in MDD and suggested possible therapeutic options for the disease.

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“…An increase of BDNF-4 has been observed in the PFC of susceptible mice exposed to chronic SD, but the same animals also showed a selective reduction of BDNF-6 transcript in the hippocampus[ 231 ]. Conversely, in another study with mice exposed to chronic SD stress, levels of BDNF in the medial PFC and hippocampus were lower in susceptible mice than in control and resilient animals[ 232 ]. Finally, several studies support the contribution of hippocampal BDNF expression to resilience to chronic stress[ 233 ].…”

Section: Advances Concerning the Neurobiological Substrates Of Resiliencementioning

confidence: 99%

Resilience to the effects of social stress on vulnerability to developing drug addiction

Calpe-López¹,

Martínez-Caballero²,

García-Pardo³

et al. 2022

WJP

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We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.

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Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents

Cited by 64 publications

References 53 publications

Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine

Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine

Inflammatory Process and Immune System in Major Depressive Disorder

Resilience to the effects of social stress on vulnerability to developing drug addiction

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