Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression

Mello, B.S.F.; Filho, Adriano José Maia Chaves; Custódio, C.S.; Rodrigues, Patrícia; Carletti, Jaqueline Vieira; Vasconcelos, Silvânia Maria Mendes; Sousa, Francisca Cléa Florenço de; Sanders, Lia Lira Olivier; Macedo, Danielle

doi:10.1016/j.jad.2021.05.083

Cited by 17 publications

(15 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results were consistent with direct interference with AβOs by doxycycline, that finally lead to reduced plaque formation. However, the drug antagonized the LPS-inducing cognitive decline in the absence of AβOs, confirming the anti-inflammatory activity described in numerous other experimental models ( Zhang et al, 2015 ; Wiggins-Dohlvik et al, 2016 ; Mello et al, 2021 ).…”

Section: Oligomers and Inflammationsupporting

confidence: 83%

Oligomeropathies, inflammation and prion protein binding

2022

View full text Add to dashboard Cite

The central role of oligomers, small soluble aggregates of misfolded proteins, in the pathogenesis of neurodegenerative disorders is recognized in numerous experimental conditions and is compatible with clinical evidence. To underline this concept, some years ago we coined the term oligomeropathies to define the common mechanism of action of protein misfolding diseases like Alzheimer, Parkinson or prion diseases. Using simple experimental conditions, with direct application of synthetic β amyloid or α-synuclein oligomers intraventricularly at micromolar concentrations, we could detect differences and similarities in the biological consequences. The two oligomer species affected cognitive behavior, neuronal dysfunction and cerebral inflammatory reactions with distinct mechanisms. In these experimental conditions the proposed mediatory role of cellular prion protein in oligomer activities was not confirmed. Together with oligomers, inflammation at different levels can be important early in neurodegenerative disorders; both β amyloid and α-synuclein oligomers induce inflammation and its control strongly affects neuronal dysfunction. This review summarizes our studies with β-amyloid or α-synuclein oligomers, also considering the potential curative role of doxycycline, a well-known antibiotic with anti-amyloidogenic and anti-inflammatory activities. These actions are analyzed in terms of the therapeutic prospects.

show abstract

Section: Oligomers and Inflammationsupporting

confidence: 83%

Oligomeropathies, inflammation and prion protein binding

2022

View full text Add to dashboard Cite

show abstract

“…However, it is reported that low-dose doxycycline could decrease systemic inflammation (51)(52)(53). Our study found IGA score also declined after treatment and there was no correlation with the above amino acids.…”

Section: Discussioncontrasting

confidence: 58%

“…We speculated doxycycline improves neurovascular sensitivity by reducing glutamic acid and aspartic acid levels. However, it is reported that low-dose doxycycline could decrease systemic inflammation ( 49 – 51 ). Our study found IGA score also declined after treatment, and there was no correlation with the above amino acids.…”

Section: Discussionmentioning

confidence: 99%

Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea

Liu¹,

Xiao²,

Chen³

et al. 2022

JCI Insight

View full text Add to dashboard Cite

Rosacea is a chronic skin disorder characterized by abnormal neurovascular and inflammatory conditions on the central face. Despite increasing evidence suggests that rosacea is associated with metabolic disorders, the role of metabolism in rosacea pathogenesis remains unknown. Here, via targeted metabolomics approach, we characterized significantly altered metabolic signatures in rosacea patients, especially for amino acid-related metabolic pathways. Among these, glutamic acid and aspartic acid are highlighted and positively correlated with the disease severity in rosacea patients. We further demonstrated that glutamic acid and aspartic acid can facilitate the development of erythema and telangiectasia, typical features of rosacea, in the skin of mice. Mechanistically, glutamic acid and aspartic acid stimulate the production of vasodilation-related neuropeptides from peripheral neuron and keratinocytes, and induce the release of nitric oxide from endothelial cells and keratinocytes. Interestingly, we provided evidence showing that doxycycline can improve the symptoms of rosacea patients possibly by targeting amino acid metabolic pathway. These findings reveal that abnormal amino acid metabolism promotes neurovascular reactivity in rosacea, and raise the possibility of targeting dysregulated metabolism as a promising strategy for clinical treatment.

show abstract

“…Treatment with classic antidepressants and immunomodulatory drugs, such as doxycycline, attenuate these microglial changes and depressive-like behavior [71,72].…”

Section: Discussionmentioning

confidence: 99%

R- and S-ketamine abrogate lipopolysaccharide-induced depressive-like behavior through microglial modulation: a differential anti-inflammatory and neurotrophic effect of the enantiomers

Filho

Lós

Soares

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Depression is a disabling mental disorder associated with increased proinflammatory cytokines and glial activation. Ketamine (KET), a racemic mixture of the R- and S-KET enantiomers, emerged as a rapid antidepressant drug. This study investigates the microglial modulatory and synaptogenic effects of R- and S-KET in a lipopolysaccharide (LPS)-induced depression model. Male rats were challenged with LPS and, 24h later, received R-KET or S-KET (10 mg/kg, IP). Two h later, these animals were evaluated for depression-like behaviors and adverse psychomimetic effects. Also, BV2 microglial cultures were challenged with LPS and exposed to R- or S-KET. Both enantiomers reversed LPS-induced depression-like behaviors and increased plasma corticosterone. LPS caused intense hippocampal glial activation, demonstrated by microglial (Iba1) and astrocytic (GFAP) markers, accompanied by increased nitrite, pro-inflammatory cytokines TNFα and IL-6, and M1 microglial phenotype markers (iNOS and CD86 mRNA). Both enantiomers attenuated Iba1 and GFAP hippocampal increase, but only S-KET induced an M2 phenotype, indicated by the higher arginase activity, IL-4, IL-10, and expression of M2a response genes (LGLAS3 and IGF-1). In the BV2 cells, S-KET increased arginase activity, IL-4, and IL-10 levels. Both enantiomers reversed the LPS-induced changes in synaptic ultrastructure and synaptosome viability. Only S-KET increased the density and the presence of mature spines in the dentate gyrus. Also, S-KET increased hippocampal BDNF maturation and boosted its secretion by BV2 microglia. Therefore, the present study demonstrated, for the first time, the unique immunomodulatory profile of S-KET, promoting a reparative M2 phenotype and protecting synaptic structures from the LPS-associated damage.

show abstract

Doxycycline at subantimicrobial dose combined with escitalopram reverses depressive-like behavior and neuroinflammatory hippocampal alterations in the lipopolysaccharide model of depression

Cited by 17 publications

References 86 publications

Oligomeropathies, inflammation and prion protein binding

Oligomeropathies, inflammation and prion protein binding

Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea

R- and S-ketamine abrogate lipopolysaccharide-induced depressive-like behavior through microglial modulation: a differential anti-inflammatory and neurotrophic effect of the enantiomers

Contact Info

Product

Resources

About