Downregulation of connexin 43 potentiates amitriptyline-induced brain-derived neurotrophic factor expression in primary astrocytes through lysophosphatidic acid receptor1/3, Src, and extracellular signal-regulated kinase

Tokunaga, Nozomi; Takimoto, Tomoyo; Nakamura, Yoki; Hisaoka-Nakashima, Kazue; Morioka, Norimitsu

doi:10.1016/j.ejphar.2022.174986

Cited by 9 publications

(4 citation statements)

References 38 publications

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“…On the other hand, an unambiguous inhibitory action of SSRIs but also of norepinephrine reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors on HC functional activity has been reported [ 13 ]. Moreover, evidence suggests that the genetic or pharmacological inactivation of Cx43 potentiates the response of antidepressant drugs at the behavioral, neurochemical and electrophysiological levels [ 14 , 27 ]. Consequently, these findings led us to envision that antidepressant drugs may favor the opening of GJs [ 11 ] but compromise HC function [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal

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Vasile

Zapata

et al. 2022

IJMS

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Studies suggest that astrocytic connexins (Cx) have an important role in the regulation of high brain functions through their ability to establish fine-tuned communication with neurons within the tripartite synapse. In light of these properties, growing evidence suggests a role of Cx in psychiatric disorders such as major depression but also in the therapeutic activity of antidepressant drugs. However, the real impact of Cx on treatment response and the underlying neurobiological mechanisms remain yet to be clarified. On this ground, the present study was designed to evaluate the functional activity of Cx in a mouse model of depression based on chronic corticosterone exposure and to determine to which extent their pharmacological inactivation influences the antidepressant-like activity of venlafaxine (VENLA). On the one hand, our results indicate that depressed mice have impaired Cx-based gap-junction and hemichannel activities. On the other hand, while VENLA exerts robust antidepressant-like activity in depressed mice; this effect is abolished by the pharmacological inhibition of Cx with carbenoxolone (CBX). Interestingly, the combination of VENLA and CBX is also associated with a higher rate of relapse after treatment withdrawal. To our knowledge, this study is one of the first to develop a model of relapse, and our results reveal that Cx-mediated dynamic neuroglial interactions play a critical role in the efficacy of monoaminergic antidepressant drugs, thus providing new targets for the treatment of depression.

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Section: Discussionmentioning

confidence: 99%

Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal

Portal

Vasile

Zapata

et al. 2022

IJMS

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“…Astroglia is also major population in the CNS and is involved BDNF-related molecules. Tokunaga et al (2022) examined the relationship among connexin 43 (Cx43) expression and BDNF induction and antidepressants in astrocytes ( Tokunaga et al, 2022 ). They showed that amitriptyline, one of tricyclic antidepressants, enhanced expression of BDNF in Cx43-knockdown astrocytes, and lysophosphatidic acid receptor (1/3) and activation of ERK signaling is involved in the enhanced BDNF expression by amitriptyline ( Tokunaga et al, 2022 ).…”

Section: Bdnf-related Signaling and Depressionmentioning

confidence: 99%

“… Tokunaga et al (2022) examined the relationship among connexin 43 (Cx43) expression and BDNF induction and antidepressants in astrocytes ( Tokunaga et al, 2022 ). They showed that amitriptyline, one of tricyclic antidepressants, enhanced expression of BDNF in Cx43-knockdown astrocytes, and lysophosphatidic acid receptor (1/3) and activation of ERK signaling is involved in the enhanced BDNF expression by amitriptyline ( Tokunaga et al, 2022 ). Using the depression mouse models caused by chronic adreno-cortico-tropic-hormone (ACTH)- and chronic unpredictable mild stress (CUMS), fast-acting (1 h) antidepressant effects of ketamine has been reported ( Ma et al, 2022 ).…”

Section: Bdnf-related Signaling and Depressionmentioning

confidence: 99%

Involvement of brain-derived neurotrophic factor signaling in the pathogenesis of stress-related brain diseases

Numakawa,

Kajihara

2023

Front. Mol. Neurosci.

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Neurotrophins including brain-derived neurotrophic factor, BDNF, have critical roles in neuronal differentiation, cell survival, and synaptic function in the peripheral and central nervous system. It is well known that a variety of intracellular signaling stimulated by TrkB, a high-affinity receptor for BDNF, is involved in the physiological and pathological neuronal aspects via affecting cell viability, synaptic function, neurogenesis, and cognitive function. As expected, an alteration of the BDNF/TrkB system is suspected to be one of the molecular mechanisms underlying cognitive decline in cognitive diseases and mental disorders. Recent evidence has also highlighted a possible link between the alteration of TrkB signaling and chronic stress. Furthermore, it has been demonstrated that downregulation of the BDNF/TrkB system and chronic stress have a role in the pathogenesis of Alzheimer’s disease (AD) and mental disorders. In this review, we introduce current evidence showing a close relationship between the BDNF/TrkB system and the development of cognition impairment in stress-related disorders, and the possible contribution of the upregulation of the BDNF/TrkB system in a therapeutic approach against these brain diseases.

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“…LPAR1 is one of the six receptors (LPAR1-6) that are activated by lysophosphatidic acid (LPA), a bioactive phospholipid. The receptor is activated by TCAs [3][4][5] and contributes to emotional behaviors [6,7]. LPAR1-deficient mice exhibited abnormalities in hippocampal functions and showed a phenotype with depressive and anxious features [7,8].…”

Section: Introductionmentioning

confidence: 99%

G protein-biased LPAR1 agonism of prototypic antidepressants: Implication in the identification of novel therapeutic target for depression

Kajitani,

Okada-Tsuchioka,

Inoue

et al. 2023

Neuropsychopharmacol.

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Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects of TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds to the lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, and activates downstream G protein signaling, while exerting a little effect on β-arrestin recruitment. This suggests that amitriptyline acts as a G protein-biased agonist of LPAR1. This biased agonism was specific to TCAs and was not observed with other antidepressants. LPAR1 was found to be involved in the behavioral effects of amitriptyline. Notably, long-term infusion of mouse hippocampus with the potent G protein-biased LPAR agonist OMPT, but not the non-biased agonist LPA, induced antidepressant-like behavior, indicating that G protein-biased agonism might be necessary for the antidepressant-like effects. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in the hippocampus. Pathway analysis indicated that long-term treatment with OMPT activated LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. Our findings provide insights into the mechanisms underlying the non-monoaminergic antidepressant effects of TCAs and identify the G protein-biased agonism of LPAR1 as a promising target for the development of novel antidepressants.

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Downregulation of connexin 43 potentiates amitriptyline-induced brain-derived neurotrophic factor expression in primary astrocytes through lysophosphatidic acid receptor1/3, Src, and extracellular signal-regulated kinase

Cited by 9 publications

References 38 publications

Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal

Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal

Involvement of brain-derived neurotrophic factor signaling in the pathogenesis of stress-related brain diseases

G protein-biased LPAR1 agonism of prototypic antidepressants: Implication in the identification of novel therapeutic target for depression

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