Lipopolysaccharide repeated challenge followed by chronic mild stress protocol introduces a combined model of depression in rats: Reversibility by imipramine and pentoxifylline

Elgarf, Alshaimaa A.; Aboul‐Fotouh, Sawsan; Abd-Alkhalek, Hadwa A.; Tabbal, Mohamed El; Hassan, A.; Kassim, Samar K.; Hammouda, Gehad A.; Farrag, Kawthar A; Abdel‐tawab, Ahmed M.

doi:10.1016/j.pbb.2014.09.014

Cited by 50 publications

(30 citation statements)

References 60 publications

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“…It confirms the findings of previous investigators suggesting that anti-inflammatory agents and PDE inhibitors may produce an antidepressant effect in patients with MDD [30][31][32][33][34][35][36][37][38][39]. Furthermore, it agrees with the results of animal studies indicating that PTX treatment suppresses stress-induced depression-like behavior [22,23].…”

Section: Discussionsupporting

confidence: 91%

“…The rationale for its use in MDD is that it competitively inhibits PDEs, resulting in increased cAMP levels, the activation of protein kinase A (PKA), the inhibition of IL and TNF-α synthesis, and reduced inflammation [21]. In animal studies, it has been shown to improve the depression-like symptoms induced in a rat model [22], and it decreased immobility time in forced swim test in a rat model of depression [23].…”

Section: Introductionmentioning

confidence: 99%

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The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

El-Haggar

Eissa

Mostafa

et al. 2018

Psychother Psychosom

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Background: There is evidence for an association between major depressive disorder (MDD) and both inflammatory and phosphodiesterase (PDE) pathways. This study aimed to evaluate the adjunct role of the PDE inhibitor pentoxifylline (PTX), a compound with anti-inflammatory properties, in the treatment of adult patients with MDD. Methods: This was a prospective, 12-week, double-blind study of parallel groups. Eighty adult outpatients who met the DSM-IV criteria for MDD participated in the trial. Patients were required to have a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 18. Patients were allocated randomly: 40 received escitalopram 20 mg/day plus placebo while the other 40 received escitalopram 20 mg/day plus PTX (400 mg b.i.d.). Patients were assessed by a psychiatrist at baseline, and 4, 8, and 12 weeks after the medication had been started. The serum levels of TNF-α, IL-6, IL-10, BDNF, 8-OHdG, and serotonin were measured at baseline and after therapy. Results: After 8 and 12 weeks, the PTX group showed a statistically significantly greater improvement in HAM-D score compared to the control group (least squares mean difference [LSMD] –3.29, p = 0.000 and LSMD –3.49, p = 0.000, respectively). Moreover, the PTX group showed a statistically significantly greater reduction in the serum levels of TNF-α, IL-6, IL-10, and 8-OHdG along with a statistically significant increase in the levels of BDNF and serotonin in comparison with the control group after the treatment. Conclusion: The findings of this study suggest that PTX could be a promising adjunct to antidepressants in the treatment of MDD patients.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

El-Haggar

Eissa

Mostafa

et al. 2018

Psychother Psychosom

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“…The anti-inflammatory effects of combined treatment with fluoxetine and acetylsalicylic acid were mediated by NF-κB activation and p38 MAPK and ERK1/2 phosphorylation (Yang et al, 2014). In rats with combined exposure of LPS and chronic mild stress (CMS), treatment with the antidepressants imipramine and pentoxyphylline (an anti-TNF-α) were effective in reversing depressive-like behavior and the elevated KYN/TRP ratio and TNF-α gene expression induced by both LPS and CMS in the hippocampus (Elgarf et al, 2014). Agomelatine, a melatonergic antidepressant, was able to reverse LPS-induced IL-1β and IL-6 production in the brain and periphery.…”

Section: Resultsmentioning

confidence: 99%

Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies

Réus¹,

Jansen

Titus³

et al. 2015

Journal of Psychiatric Research

197

113

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Treatment-resistant depression affects up to 20% of individuals suffering from major depressive disorder (MDD). The medications currently available to treat depression, including serotonin re-uptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), fail to produce adequate remission of depressive symptoms for a large number of patients. The monoamine hypothesis upon which these medications are predicated should be expanded and revised as research elucidates alternative mechanisms of depression and effective methods to treat the underlying pathologic consequences. Research into the role of tryptophan degradation and the kynurenine pathway in the setting of inflammation has brought new insight into potential etiologies of MDD. Further investigation into the connection between inflammatory mediators, tryptophan degradation, and MDD can provide many targets for novel antidepressant therapies. Thus, this review will highlight the role of the kynurenine pathway in the pathophysiology of depression, as well as a novel therapeutic target to classic and new modulators to treat depression based on findings from preclinical and clinical studies.

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“…However, there are conflicting results regarding the effects of imipramine on the tryptophan-kynurenine pathway. One study has found that imipramine decreased the kynurenine/tryptophan ratio in vivo following a chronic LPS and stress paradigm [9], whereas an in vitro study found that imipramine had no effect on kynurenic acid and 3-hydroxykynurenine [16]. Clinically, paroxetine treatment during IFN-␣ therapy did not change tryptophan or kynurenine levels [4].…”

Section: Imipramine Reversed Ifn-˛-induced Depression-like Behaviourmentioning

confidence: 99%

Interferon-alpha treatment induces depression-like behaviour accompanied by elevated hippocampal quinolinic acid levels in rats

Fischer

Eskelund

Budac

et al. 2015

Behavioural Brain Research

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Lipopolysaccharide repeated challenge followed by chronic mild stress protocol introduces a combined model of depression in rats: Reversibility by imipramine and pentoxifylline

Cited by 50 publications

References 60 publications

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies

Interferon-alpha treatment induces depression-like behaviour accompanied by elevated hippocampal quinolinic acid levels in rats

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