Inhibition of indoleamine 2,3-dioxygenase 1/2 prevented cognitive impairment and energetic metabolism changes in the hippocampus of adult rats subjected to polymicrobial sepsis

Comim, Clarissa M.; Freiberger, Viviane; Ventura, Luisa; Mina, Francielle; Ferreira, Gabriela K.; Michels, Monique; Generoso, Jaqueline S.; Streck, Emílio L.; Quevedo, João; Barichello, Tatiana; Dal‐Pizzol, Felipe

doi:10.1016/j.jneuroim.2017.02.001

Cited by 22 publications

(15 citation statements)

References 39 publications

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“…In contrast, TDO is expressed in a significant proportion of human tumours . Therefore, compelling evidence suggests that IDO‐1 is a potential therapeutic target for the treatment of neurological diseases …”

Section: Introductionmentioning

confidence: 99%

Lithium attenuates d‐amphetamine‐induced hyperlocomotor activity in mice via inhibition of interaction between cyclooxygenase‐2 and indoleamine‐2,3‐dioxygenase

Phan

Shin

Jeong

et al. 2020

Clin Exp Pharma Physio

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In the present study, we investigated whether mood stabilizer lithium (Li) protects against d‐amphetamine (AMP)‐induced mania‐like behaviours via modulating the novel proinflammatory potential. Repeated treatment with AMP resulted in significant increases in proinflammatory cyclooxygenase‐2 (COX‐2) and indolemaine‐2,3‐dioxygenase‐1 (IDO)‐1 expression in the prefrontal cortex (PFC) of mice. However, AMP treatment did not significantly change IDO‐2 and 5‐lipoxygenase (5‐LOX) expression, suggesting that proinflammatory parameters such as COX‐2 and IDO‐1 are specific for AMP‐induced behaviours. AMP‐induced initial expression of COX‐2 (15 minutes post‐AMP) was earlier than that of IDO‐1 (1 hour post‐AMP). Mood stabilizer Li and COX‐2 inhibitor meloxicam significantly attenuated COX‐2 expression 15 minutes post‐AMP, whereas IDO‐1 inhibitor 1‐methyl‐DL‐tryptophan (1‐MT) did not affect COX‐2 expression. However, AMP‐induced IDO‐1 expression was significantly attenuated by Li, meloxicam or 1‐MT, suggesting that COX‐2 is an upstream molecule for the induction of IDO‐1 caused by AMP. Consistently, co‐immunoprecipitation between COX‐2 and IDO‐1 was observed at 30 minutes, 1, 3, and 6 hours after the final AMP treatment. This interaction was also significantly inhibited by Li, meloxicam or 1‐MT. Furthermore, AMP‐induced hyperlocomotion was significantly attenuated by Li, meloxicam or 1‐MT. We report, for the first time, that mood stabilizer Li attenuates AMP‐induced mania‐like behaviour via attenuation of interaction between COX‐2 and IDO‐1, and that the interaction of COX‐2 and IDO‐1 may be critical for the therapeutic intervention mediated by mood stabilizer.

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Section: Introductionmentioning

confidence: 99%

Lithium attenuates d‐amphetamine‐induced hyperlocomotor activity in mice via inhibition of interaction between cyclooxygenase‐2 and indoleamine‐2,3‐dioxygenase

Phan

Shin

Jeong

et al. 2020

Clin Exp Pharma Physio

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“…However, IDO-1/2 inhibition normalized the activity of these complexes in the hippocampus. Additionally, Wistar rats presented impairment of habituation and aversive memories 10 days after CLP, while the adjuvant treatment with the IDO-1/2 inhibitor prevented these alterations [75]. The results suggest that IDO-dependent neurotoxic kynurenine metabolism was a cause of sepsis-induced cognitive impairment, and IDO inhibitors might be a new avenue as adjuvant treatment for sepsisassociated encephalopathy.…”

Section: Inhibition Of Indoleamine 23-dioxygenase Pathwaymentioning

confidence: 84%

Long-Term Cognitive Outcomes After Sepsis: a Translational Systematic Review

et al. 2018

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Sepsis is systemic inflammatory response syndrome with a life-threatening organ dysfunction that is caused by an unbalanced host immune response in an attempt to eliminate invasive microorganisms. We posed questions, "Does sepsis survivor patients have increased risk of neuropsychiatric manifestations?" and "What is the mechanism by which sepsis induces long-term neurological sequelae, particularly substantial cognitive function decline in survivor patients and in pre-clinical sepsis models?" The studies were identified by searching PubMed/MEDLINE (National Library of Medicine), PsycINFO, EMBASE (Ovid), LILACS (Latin American and Caribbean Health Sciences Literature), IBECS (Bibliographical Index in Spanish in Health Sciences), and Web of Science databases for peer-reviewed journals that were published until January 2018. A total of 3555 papers were included in the primary screening. After that, 130 articles were selected for the study. A number of pre-clinical studies have shown an auto amplification of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 in the first few hours after sepsis induction, also increased blood-brain barrier permeability, elevated levels of matrix metalloproteinases, increased levels of damage-associated molecular patterns were demonstrated. In addition, the rodents presented long-term cognitive impairment in different behavioral tasks that were prevented by blocking the mechanism of action of these inflammatory mediators. Clinical studies have showed that sepsis survivors presented increased bodily symptoms such as fatigue, pain, visual disturbances, gastrointestinal problems, and neuropsychiatric problems compared to before sepsis. Sepsis leaves the survivors with an aftermath of physiological, neuropsychiatric, and functional impairment. Systematic review registration: CRD42017071755.

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“…9 Furthermore, Kyn is induced by pro-inflammatory cytokines, but notably also gives rise to metabolites that suppress inflammation, indicating a complex relationship. 37 There is ample evidence that IDO activation has a negative impact on cognitive function in rodent models [4][5][6][7] and can exacerbate AD pathology in amyloid knock-in mice. 5 However, it is less clear how IDO activity outside the brain relates to cognitive function.…”

Section: Discussionmentioning

confidence: 99%

“…1 The kynurenine pathway is most highly expressed not only in liver and monocytes 2 but also in muscle, brain, and intestine. 3 The kynurenines and the ratelimiting enzyme indoleamine 2,3-dioxygenase (IDO) of the kynurenine pathway have been implicated in experimental cognitive dysfunction in mice, [4][5][6][7] and kynurenines are lower in Alzheimer's disease (AD) compared with healthy controls. 8 Tryptophan 2,3-dioxygenase (TDO) and IDO generate kynurenine (Kyn) from Trp, 9 which gives rise to downstream metabolites that have shown neuroprotective (kynurenic acid [KA]) 10 and neurotoxic properties (quinolinic acid [QA]).…”

Section: Introductionmentioning

confidence: 99%

“…1 The kynurenine pathway is most highly expressed not only in liver and monocytes 2 but also in muscle, brain, and intestine. 3 The kynurenines and the rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO) of the kynurenine pathway have been implicated in experimental cognitive dysfunction in mice, 4-7 and kynurenines are lower in Alzheimer’s disease (AD) compared with healthy controls. 8…”

Section: Introductionmentioning

confidence: 99%

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Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia

Solvang

Nordrehaug

Aarsland

et al. 2019

Int J�Tryptophan�Res

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Introduction: Circulating tryptophan (Trp) and its downstream metabolites, the kynurenines, are potentially neuroactive. Consequently, they could be associated with neuropsychiatric symptoms and cognitive prognosis in patients with dementia. Objective: The objective of this study was to assess associations between circulating kynurenines, cognitive prognosis, and neuropsychiatric symptoms. Methods: We measured baseline serum Trp, neopterin, pyridoxal 5′-phosphate (PLP), and 9 kynurenines in 155 patients with mild dementia (90 with Alzheimer’s disease, 65 with Lewy body dementia). The ratios between kynurenine and Trp and kynurenic acid (KA) to kynurenine (KKR) were calculated. The Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI) were administered at baseline and annually over 5 years. Associations between baseline metabolite concentrations with MMSE and the NPI total score were assessed using a generalized structural equation model (mixed-effects multiprocess model), adjusted for age, sex, current smoking, glomerular filtration rate, and PLP. Post hoc associations between KKRs and individual NPI items were assessed using logistic mixed-effects models. False discovery rate (0.05)–adjusted P values ( Q values) are reported. Results: Kynurenine had a nonlinear quadratic relationship with the intercept of the MMSE scores over 5 years ( Q < 0.05), but not with the slope of MMSE decline. Kynurenine was associated with a higher NPI total score over time ( Q < 0.001). Post hoc, both KKR and KA were associated with more hallucinations ( Q < 0.05). Conclusions: Kynurenine has a complex relationship with cognition, where both low and high levels were associated with poor cognitive performance. A higher KKR indicated risk for neuropsychiatric symptoms, especially hallucinations.

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Inhibition of indoleamine 2,3-dioxygenase 1/2 prevented cognitive impairment and energetic metabolism changes in the hippocampus of adult rats subjected to polymicrobial sepsis

Cited by 22 publications

References 39 publications

Lithium attenuates d‐amphetamine‐induced hyperlocomotor activity in mice via inhibition of interaction between cyclooxygenase‐2 and indoleamine‐2,3‐dioxygenase

Lithium attenuates d‐amphetamine‐induced hyperlocomotor activity in mice via inhibition of interaction between cyclooxygenase‐2 and indoleamine‐2,3‐dioxygenase

Long-Term Cognitive Outcomes After Sepsis: a Translational Systematic Review

Kynurenines, Neuropsychiatric Symptoms, and Cognitive Prognosis in Patients with Mild Dementia

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