7,8‐dihydroxyflavone, a TrkB receptor agonist, blocks long‐term spatial memory impairment caused by immobilization stress in rats

Andero, Raül; Daviu, Núria; Escorihuela, Rosa M.; Nadal, Roser; Armario, Antonio

doi:10.1002/hipo.20906

Cited by 99 publications

(86 citation statements)

References 43 publications

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“…All samples to be statistically compared were run in the same assay to avoid inter-assay variability. Plasma corticosterone levels ( Figure 1) were determined by doubleantibody radioimmunoassay as previously described (Andero et al, 2012). Corticosterone radioimmunoassay used 125 I-corticosteronecarboximethyloximetyrosine-methyl ester (ICN-Biolink 2000, Barcelona, Spain), synthetic corticosterone (Sigma, Barcelona, Spain) as the standard, and an antibody raised in rabbits against corticosteronecarboximethyloxime-BSA kindly provided by Dr G. Makara (Institute of Experimental Medicine, Budapest, Hungary).…”

Section: Radioimmunoassaysmentioning

confidence: 99%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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Posttraumatic stress disorder (PTSD) is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symptom relapse. In the present study, we used a putative animal model of PTSD that included presentation of immobilization stress (IMO) followed by fear conditioning (FC) a week later. We then investigated the acute effects of GR receptor activation on the extinction (EXT) of conditioned freezing, using dexamethasone administered systemically which is known to result in suppression of the HPA axis. In our previous work, IMO followed by tone-shockmediated FC was associated with impaired fear EXT. In this study, we administered dexamethasone 4 h before EXT training and then examined EXT retention (RET) 24 h later to determine whether dexamethasone suppression rescued EXT deficits. Dexamethasone treatment produced dose-dependent enhancement of both EXT and RET. Dexamethasone was also associated with reduced amygdala Fkbp5 mRNA expression following EXT and after RET. Moreover, DNA methylation of the Fkbp5 gene occurred in a dose-dependent and time course-dependent manner within the amygdala. Additionally, we found dynamic changes in epigenetic regulation, including Dnmt and Tet gene pathways, as a function of both fear EXT and dexamethasone suppression of the HPA axis. Together, these data suggest that dexamethasone may serve to enhance EXT by altering Fkbp5-mediated glucocorticoid sensitivity via epigenetic regulation of Fkbp5 expression.

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Section: Radioimmunoassaysmentioning

confidence: 99%

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Sawamura

Klengel

Armario

et al. 2015

Neuropsychopharmacol

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“…Two hours after the last administration, the mice were subjected to behavioral testing. The dosage of 5 mg/kg 7,8-DHF and a 2-h interval between the last drug treatment and assays were chosen on the basis of previous in vivo studies (Andero et al, 2010;Andero et al, 2011;Jang et al, 2010;Liu et al, 2010), which demonstrated central TrkB activation, enhanced neurogenesis, and related behavioral changes in mice or rats treated with systemic 7,8-DHF administration.…”

Section: Drug Treatmentsmentioning

confidence: 99%

“…Remarkably, systemic administration of 7,8-DHF can activate TrkB receptors in brains as evidenced by increases in phosphorylated TrkB, and induce BDNF-like behavioral phenotypes such as enhanced learning and memory, and antistress or antidepressant-like effects in rodents (Andero et al, 2010;Andero et al, 2011;Choi et al, 2010;Jang et al, 2010;Liu et al, 2010). Therefore, the small-molecule TrkB receptor agonist 7,8-DHF represents a novel and useful tool to investigate the role of BDNFTrkB signaling in vivo.…”

Section: Introductionmentioning

confidence: 99%

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Devi

Ohno

2011

Neuropsychopharmacol

253

188

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Increasing evidence suggests that reductions in brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) may have a role in the pathogenesis of Alzheimer's disease (AD). However, the efficacy and safety profile of BDNF therapy (eg, gene delivery) remains to be established toward clinical trials. Here, we evaluated the effects of 7,8-dihydroxyflavone (7,8-DHF), a recently identified small-molecule TrkB agonist that can pass the blood-brain barrier, in the 5XFAD transgenic mouse model of AD. 5XFAD mice at 12-15 months of age and non-transgenic littermate controls received systemic administration of 7,8-DHF (5 mg/kg, i.p.) once daily for 10 consecutive days. We found that 7,8-DHF rescued memory deficits of 5XFAD mice in the spontaneous alternation Y-maze task. 5XFAD mice showed impairments in the hippocampal BDNF-TrkB pathway, as evidenced by significant reductions in BDNF, TrkB receptors, and phosphorylated TrkB. 7,8-DHF restored deficient TrkB signaling in 5XFAD mice without affecting endogenous BDNF levels. Meanwhile, 5XFAD mice exhibited elevations in the b-secretase enzyme (BACE1) that initiates amyloid-b (Ab) generation, as observed in sporadic AD. Interestingly, 7,8-DHF blocked BACE1 elevations and lowered levels of the b-secretasecleaved C-terminal fragment of amyloid precursor protein (C99), Ab40, and Ab42 in 5XFAD mouse brains. Furthermore, BACE1 expression was decreased by 7,8-DHF in wild-type mice, suggesting that BDNF-TrkB signaling is also important for downregulating baseline levels of BACE1. Together, our findings indicate that TrkB activation with systemic 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and b-amyloidogenesis.

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“…This stressor has been extensively characterized in our laboratory (Belda et al, 2008b) and has been determined to induce changes in activity and anxiety that can last for some days (Belda et al, 2008a), as well as more protracted impairment of spatial memory in the Morris water maze (Andero et al, 2012) and fear extinction (Andero et al, 2011).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…group in rats (i.e., Andero et al, 2012;Belda et al, 2008a;Belda et al, 2012;, Daviu et al, 2014Gagliano et al, 2008;Muñoz-Abellán et al, 2008;Muñoz-Abellán et al, 20011) and mice (Amador-Arjona et al, 2010;Andero et al, 2011).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats

Fuentes

Carrasco

Armario

et al. 2014

Hormones and Behavior

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Exposure to stress during childhood and adolescence increases vulnerability to developing several psychopathologies in adulthood and alters the activity of the hypothalamic-pituitaryadrenal (HPA) axis, the prototypical stress system. Rodent models of juvenile stress appear to support this hypothesis because juvenile stress can result in reduced activity/exploration and enhanced anxiety, although results are not always consistent. Moreover, an in-depth characterization of changes in the HPA axis is lacking. In the present study, the long-lasting effects of juvenile stress on adult behavior and HPA function were evaluated in male rats. The juvenile stress consisted of a combination of stressors (cat odor, forced swim and footshock) during postnatal days 23-28. Juvenile stress reduced the maximum amplitude of the adrenocorticotropic hormone (ACTH) levels (reduced peak at lights off), without affecting the circadian corticosterone rhythm, but other aspects of the HPA function (negative glucocorticoid feedback, responsiveness to further stressors and brain gene expression of corticotrophin-releasing hormone and corticosteroid receptors) remained unaltered. The behavioral effects of juvenile stress itself at adulthood were modest (decreased activity in the circular corridor) with no evidence of enhanced anxiety. Imposition of an acute severe stressor (immobilization on boards, IMO) did not increase anxiety in control animals, as evaluated one week later in the elevated-plus maze (EPM), but it potentiated the acoustic startle response (ASR). However, acute IMO did enhance anxiety in the EPM, in juvenile stressed rats, thereby suggesting that juvenile stress sensitizes rats to the effects of additional stressors.

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7,8‐dihydroxyflavone, a TrkB receptor agonist, blocks long‐term spatial memory impairment caused by immobilization stress in rats

Cited by 99 publications

References 43 publications

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats

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