Major depression model induced by repeated and intermittent lipopolysaccharide administration: Long-lasting behavioral, neuroimmune and neuroprogressive alterations

Rodrigues, Francisca; Souza, Marcos Romário Matos de; Lima, Camila Nayane de Carvalho; Silva, Francisco Eliclécio Rodrigues da; Costa, Deiziane Viana da Silva; Santos, Cláudio Costa dos; Miyajima, Fábio; Sousa, Francisca Cléa Florenço de; Vasconcelos, Silvânia Maria Mendes; Barichello, Tatiana; Quevedo, João; Maes, Michaël; Lucena, David Freitas de; Macedo, Danielle

doi:10.1016/j.jpsychires.2018.10.003

Cited by 50 publications

(35 citation statements)

References 52 publications

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“…The present study is supportive of those findings and showed that FLX increased 5-HT levels and inhibited TNF-α mRNA expression. These findings are consistent with previous reports that FLX improved depressive behavior partly through its anti-inflammatory effects (44, 45). As with the similar effect in depression treatment, FLX alleviated pain through its serotonergic antinociceptive effects and its intrinsic anti-inflammatory effect (22).…”

Section: Discussionsupporting

confidence: 93%

Comorbidity of Pain and Depression in a Lumbar Disc Herniation Model: Biochemical Alterations and the Effects of Fluoxetine

Cai

Lu³

et al. 2019

Front. Neurol.

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Summary of Background Data: Depression is one of the most common comorbidities in patients with chronic low back pain. However, the mechanisms of depression in chronic low back pain patients and the effect of antidepressants on the comorbidity of pain and depression need to be further explored. The establishment of the appropriate animal models and of more effective therapies is critical for this comorbidity. Lumbar disc herniation (LDH) is the most common disease that causes low back pain. The current study examined whether an LDH model shows behavioral and biochemical alterations that are in accordance with the characteristics of the comorbidity of pain and depression and tested the effect of fluoxetine (FLX) on these measures.Objective: The current study examined whether an LDH model showed the behavioral and biochemical alterations that were in accordance with the characteristics of the comorbidity of pain and depression and tested the effect of FLX on these measures.Methods: The LDH animal model was generated by the implantation of the autologous nucleus pulposus on the left L5 nerve root just proximal to the dorsal root ganglion in Wistar rats. Pain intensity was evaluated by mechanical allodynia and thermal hyperalgesia, and changes in depressive behavior were examined by the taste preference and forced swim tests. Hippocampal serotonin (5-HT) levels were measured by liquid chromatography-mass spectrometry, and tumor necrosis factor-α (TNF-α) mRNA was quantified using real-time reverse transcriptase PCR.Results: LDH resulted in chronic pain, which further induced depressive behavior that persisted for 6 weeks after surgery. There were decreased 5-HT concentrations and upregulated TNF-α mRNA levels that were accompanied by behavioral changes. FLX treatment improved depressive behavior and moderately alleviated pain through increased 5-HT concentrations, and inhibited TNF-α mRNA expression.Conclusions: In summary, our studies provide initial evidence that the LDH chronic pain model might serve as a model of the comorbidity of low back pain and depression. The finding that FLX improved depressive behavior and pain through normalized 5-HT concentrations and TNF-α mRNA expression establishes the initial mechanism of the comorbidity of pain and depression.

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Section: Discussionsupporting

confidence: 93%

Comorbidity of Pain and Depression in a Lumbar Disc Herniation Model: Biochemical Alterations and the Effects of Fluoxetine

Cai

Lu³

et al. 2019

Front. Neurol.

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“…This theory is corroborated by findings that increased root canal endotoxin in subjects with chronic apical periodontitis is associated with increased nitro-oxidative stress and depressive symptoms (Gomes et al, 2018). Moreover, repeated and intermittent administration of LPS may induce depressive-like behaviours in the rodent in association with increased microglial activation and increased levels of nuclear factor-kB, superoxide and cytokine production, lowered tryoptophan and increased neurotoxic tryptophan catabolites (Kubera et al, 2013;Rodrigues et al, 2018). Administration of LPS to humans not only induces the levels of pro-and anti-inflammatory cytokines, but also lowers mood, and induces anxiety and social disconnection (Eisenberger et al, 2010;Grigoleit et al, 2011).…”

Section: Discussionmentioning

confidence: 78%

The menstrual cycle may not be limited to the endometrium but also may impact gut permeability

Roomruangwong

Carvalho

Geffard³

et al. 2019

Acta Neuropsychiatr.

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Objective:To examine associations between IgA responses to Gram-negative gut commensal bacteria and peri-menstrual symptoms and sex hormone levels during the menstrual cycle in women with and without premenstrual symptoms.Methods:Forty women aged 18–45 years completed the Daily Record of Severity of Problems (DRSP) during all 28 consecutive days of the menstrual cycle. We assayed, in plasma, IgA responses to six Gram-negative bacteria, that is, Hafnei alvei, Pseudomonas aeruginosa, Morganella morganii, Klebsiella pneumoniae, Pseudomonas putida and Citobacter koseri, progesterone and oestradiol at days 7, 14, 21 and 28 of the menstrual cycle.Results:Significant changes in Δ (actual − 1 week earlier) IgA to lipopolysaccharides (LPS) of the six Gram-negative bacteria during the menstrual cycle were observed with peak IgA levels at T4 (day 28) and lows at T1 or T2 (day 7 or 14). The ΔIgA changes in H. alvei, M. Morganii, P. putida during the menstrual cycle were significantly and positively associated with changes in the total DRSP score, and severity of physio-somatic, anxiety and breast-craving, but not depressive, symptoms. The changes in IgA responses to LPS were largely predicted by changes in progesterone and steady-state levels of progesterone averaged over the luteal phase.Discussion:Menstrual cycle-associated changes in IgA directed against LPS and by inference bacterial translocation may be driven by the effects of progesterone on transcellular, paracellular and vascular pathways (leaky gut) thereby contributing to the severity of physio-somatic and anxiety symptoms as well as fatigue, breast swelling and food cravings.

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“…It is also possible that increased translocation of LPS may explain the development of melancholia symptoms. In this respect, animal models show that chronic and/or repeated administration of LPS may induce long-lasting changes in neuro-oxidative and neuro-immune pathways (similar as those detected in MDD) in association with anhedonia, a key symptom of melancholia (Kubera et al, 2013;Rodrigues et al, 2018). LPS may cause depressive-like or melancholia symptoms via different routes, including PAMP-activation of the TLR complex with consequent production of reactive oxygen and nitrogen species and pro-inflammatory cytokines leading to oxidative and nitrosative stress as well as activated immune-inflammatory pathways (Lucas & Maes, 2013;Lucas et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…As such, LPS or bacterial translocation may cause immune, inflammatory and oxidative stress responses. Furthermore, injection of even minimal amounts of LPS to human volunteers may decrease mood and induce anxiety (Eisenberger et al, 2010;Grigoleit et al, 2011), while, in animal models, repeated administration of LPS induces depressive-like behaviors as well as neuro-inflammatory responses (Kubera et al, 2013;Rodrigues et al, 2018). There are now also data that alterations in microbial composition in the gut, indicating gut dysbiosis, may occur in psychiatric disorders including MDD (Aizawa et al, 2016;Jiang et al, 2015;Lin et al, 2017;Naseribafrouei et al, 2014) and BD (Nguyen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia is Present

Simeonova

Stoyanov

Leunis³

et al. 2019

Preprint

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Major depression (MDD) is accompanied by higher serum IgM/IgA responses to LPS of Gram-negative bacteria, suggesting increased bacterial translocation and gut dysbiosis. Gut dysbiosis may occur in bipolar disorder (BD) and there are differences between MDD and BD type 1 (BP1) and -2 (BP2) in nitro-oxidative stress biomarkers associated with leaky gut. This study examines serum IgM/IgA responses directed to LPS of 6 Gram-negative bacteria in 29 BP1, 37 BP2, 44 MDD and 30 healthy individuals. MDD plus BD was best discriminated from controls by increased IgM/IgA responses to Pseudomonas aeruginosa. BP1 patients showed higher IgM responses to Morganella morganii as compared with MDD and BP2 patients. Patients with melancholia showed higher IgA responses to Citrobacter koseri as compared to controls and non-melancholic depression. The total score on the Hamilton Depression Rating Scale was significantly associated with IgA responses, especially C. koseri. IgG responses to oxidized low-density lipoprotein were significantly associated with signs of increased bacterial translocation. In conclusion, not only MDD but also BP1 and BP2 are accompanied by an immune response due to the increased load of plasma LPS of gut commensal bacteria while these aberrations in the gut-brain axis are most pronounced in BP1 and patients with melancholic features. Activated oxidative stress pathways and autoimmune responses to oxidative specific epitopes in mood disorders may be driven by a breakdown in gut paracellular, transcellular and/or vascular pathways. If replicated, drugs that protect the integrity of the gut barrier may offer novel therapeutic opportunities for BP1 and MDD.

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Major depression model induced by repeated and intermittent lipopolysaccharide administration: Long-lasting behavioral, neuroimmune and neuroprogressive alterations

Cited by 50 publications

References 52 publications

Comorbidity of Pain and Depression in a Lumbar Disc Herniation Model: Biochemical Alterations and the Effects of Fluoxetine

Comorbidity of Pain and Depression in a Lumbar Disc Herniation Model: Biochemical Alterations and the Effects of Fluoxetine

The menstrual cycle may not be limited to the endometrium but also may impact gut permeability

Increased Serum Immunoglobulin Responses to Gut Commensal Gram-Negative Bacteria in Unipolar Major Depression and Bipolar Disorder Type 1, Especially When Melancholia is Present

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