Chronic administration of methylmalonate on young rats alters neuroinflammatory markers and spatial memory

Ribeiro, Leandro Rodrigo; Della-Pace, Iuri Domingues; Ferreira, Ana Paula de Oliveira; Funck, Vinícius Rafael; Pinton, Simone; Bobinski, Franciane; Oliveira, Clarissa Vasconcelos de; Fiorin, Fernando da Silva; Furian, Ana Flávia; Oliveira, Mauro Schneider; Nogueira, Cristina W.; Santos, Adair R.S.; Royes, Luiz Fernando Freire; Fighera, Michele Rechia

doi:10.1016/j.imbio.2013.04.008

Cited by 27 publications

(11 citation statements)

References 76 publications

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“…Through participating in hypothalamic-pituitary-adrenal axis hyperactivity, IL-1β has been shown to cause depression 50 51 . In addition, IL-1β has been closely correlated with spatial and associative memory injury in previous studies 52 53 . In our study, IL-1β was significantly elevated in the CP/CPPS group and was positively correlated with SAS and SDS.…”

Section: Discussionmentioning

confidence: 66%

The role of inflammatory cytokines and ERK1/2 signaling in chronic prostatitis/chronic pelvic pain syndrome with related mental health disorders

Yang

Zhao

et al. 2016

Sci Rep

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Mental health disorders(MHD) in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been widely studied. However, the underlying role of inflammatory cytokines and their associated signaling pathways have not been investigated. Here, we report the potential role of cytokines and associated signaling pathways in CP/CPPS patients with MHD and in a CP/CPPS animal model. CP/CPPS patients (n = 810) and control subjects (n = 992) were enrolled in this case-control multicenter study, and serum cytokine levels were measured. Male Sprague-Dawley rats received multiple intracutaneous injections of an immuno-agent along with a pertussis-diphtheria-tetanus triple vaccine for autoimmune CP/CPPS development. The results revealed that, in CP/CPPS patients with significant MHD, elevated IL-1α, IL-1β, IL-4, IL-13, and TNF-α serum levels were observed. The above five cytokines in CP/CPPS rats were significantly elevated in prostate tissue (p < 0.05), and IL-1β levels were elevated in serum and cerebrospinal fluid. In behavioral tests, CP/CPPS rats showed anxiety- and depression-like symptoms, and impaired spatial and associative memory performance (p < 0.05). In the CP/CPPS group, ERK1/2 phosphorylation levels were increased in the amygdala and nucleus accumbens, and decreased in the hippocampus, but not caudate nucleus. Thus, prostate-derived cytokines, especially IL-1β, cross the blood brain barrier and may lead to enhanced ERK1/2 signaling in several brain areas, possibly underlying induction of CP/CPPS-related MHD.

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Section: Discussionmentioning

confidence: 66%

The role of inflammatory cytokines and ERK1/2 signaling in chronic prostatitis/chronic pelvic pain syndrome with related mental health disorders

Yang

Zhao

et al. 2016

Sci Rep

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“…To the best of our knowledge, the association between AF, neurocognitive function and the inflammatory markers, IL-1RA, IL-9, IL-12 and MIP-1β, has not previously been studied. In a recent study in rats, Ribeiro demonstrated that induction of a pro-inflammatory state by administration of metylmalonic acid resulted in increased levels of interleukin-1β(IL-1ß) and tumor necrosis factor-α (TNF-α), both in blood and in the cerebral cortex of the animals, as well as a reduction in spatial orientation [37]. …”

Section: Discussionmentioning

confidence: 99%

Improved neurocognitive functions correlate with reduced inflammatory burden in atrial fibrillation patients treated with intensive cholesterol lowering therapy

Lappegård

Pop-Purceleanu

Sexton

et al. 2013

J Neuroinflammation

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BackgroundAtrial fibrillation (AF) is associated with increased mortality and morbidity, including risk for cerebral macro- and microinfarctions and cognitive decline, even in the presence of adequate oral anticoagulation. AF is strongly related to increased inflammatory activity whereby anti-inflammatory agents can reduce the risk of new or recurrent AF. However, it is not known whether anti-inflammatory therapy can also modify the deterioration of neurocognitive function in older patients with AF. In the present study, older patients with AF were treated with intensive lipid-lowering therapy with atorvastatin 40 mg and ezetimibe 10 mg, or placebo. We examined the relationship between neurocognitive functions and inflammatory burden.FindingsAnalysis of inflammatory markers revealed significant reductions in high sensitivity C-reactive protein (hs-CRP), fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 receptor antagonist (IL-1RA), interleukin (IL)-9, IL-13 and IL-17, and interferon-γ (IFNγ) in the treatment group compared to placebo. Reduction in plasma concentration of IL-1RA, IL-2, IL-9 and IL-12, and macrophage inflammatory protein-1β (MIP-1β) correlated significantly with improvement in the neurocognitive functions memory and speed. Loss of volume in amygdala and hippocampus, as determined by magnetic resonance imaging (MRI), was reduced in the treatment arm, statistically significant for left amygdala.ConclusionsAnti-inflammatory therapy through intensive lipid-lowering treatment with atorvastatin 40 mg and ezetimibe 10 mg can modify the deterioration of neurocognitive function, and the loss of volume in certain cerebral areas in older patients with AF.Trial registration Clinical Trials.govNCT00449410

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Section: Introductionmentioning

confidence: 99%

“…Several previous studies showed neuroinflammation and unbalance of redox homeostasis in the central nervous system (CNS) were important mechanisms for MMA-induced cognitive impairment [10][11][12][13][14][15]. In addition, the peripheral blood immune cells, such as lymphocytes and monocytes, increased relatively in MMA patients [12,[16][17][18]. Meanwhile, the accumulation of methylmalonic acid in the blood induced the increase in pro-inflammatory cytokines and oxidative substances in both CNS and blood serum [12].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the peripheral blood immune cells, such as lymphocytes and monocytes, increased relatively in MMA patients [12,[16][17][18]. Meanwhile, the accumulation of methylmalonic acid in the blood induced the increase in pro-inflammatory cytokines and oxidative substances in both CNS and blood serum [12]. So we speculated increase of cytokines and oxidative substances in the CNS might be a consequence of this inflammatory response in the periphery.…”

Section: Introductionmentioning

confidence: 99%

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Determination of Cytokines and Oxidative Stress Biomarkers in Cognitive Impairment Induced by Methylmalonic Acidemia

Hong

Liu

et al. 2021

Neuroimmunomodulation

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Objective: Methylmalonic acidemia (MMA) is the most common organic acidemia in children. Many patients with MMA suffered from cognitive impairments. The aim of this study was to identify the significance of cytokines and oxidative stress biomarkers in MMA-induced cognitive impairment. Methods: We enrolled 64 children with combined MMA and homocystinuria and 64 age- and sex-matched healthy volunteers. Participants were subsequently classified as with or without cognitive impairments using a uniform neuropsychological assessment test. Serum samples were collected. The serum levels of cytokines and oxidative stress biomarkers were measured using the ELISA or chemical methods. Results: Compared to control group, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, malondialdehyde (MDA), and nitric oxide (NO) in the MMA patients increased markedly (p < 0.05); glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (p < 0.01). The levels of IL-6, TNF-α, NO, and MDA in the serum were negatively associated with DQ or IQ scores. The levels of GSH and SOD in the serum were positively correlated with DQ or IQ scores. After receiver operating characteristic curve analysis, NO was the most useful individual marker for distinguishing the cognitive dysfunction, corresponding to the area under ROC curve (AUC) of 0.82 (95% CI, 0.74–0.91), sensitivity of 76.60%, and specificity of 80.25%. GSH and MDA were also useful for diagnosis of MMA-induced cognitive dysfunction, corresponding to the AUC of 0.80 (95% CI, 0.70–0.89), and 0.73 (95% CI, 0.63–0.82), respectively. The sensitivity and specificity of GSH were 72.34 and 80.25%, respectively. The sensitivity and specificity of MDA were 85.11 and 51.85%, respectively. Conclusions: The high-concentration methylmalonic acid in the blood induced immune cells to release pro-inflammatory cytokines such as TNF-α and IL-6. These cytokines and high-concentration methylmalonic acid stimulated the immune cells to produce reactive oxygen species (ROS) and reactive nitrogen species (RNS). The serum methylmalonic acid, cytokines, ROS, and RNS were across the blood-brain barrier and induced cognitive impairment. The small molecule substances such as serum NO, MDA, and GSH participated in the process of neuroinflammation and oxidative stress injury induced by MMA and could be useful for distinguishing the cognitive impairment.

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Chronic administration of methylmalonate on young rats alters neuroinflammatory markers and spatial memory

Cited by 27 publications

References 76 publications

The role of inflammatory cytokines and ERK1/2 signaling in chronic prostatitis/chronic pelvic pain syndrome with related mental health disorders

The role of inflammatory cytokines and ERK1/2 signaling in chronic prostatitis/chronic pelvic pain syndrome with related mental health disorders

Improved neurocognitive functions correlate with reduced inflammatory burden in atrial fibrillation patients treated with intensive cholesterol lowering therapy

Determination of Cytokines and Oxidative Stress Biomarkers in Cognitive Impairment Induced by Methylmalonic Acidemia

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