Itaconate alleviates β2-microglobulin-induced cognitive impairment by enhancing the hippocampal amino-β-carboxymuconate-semialdehyde-decarboxylase/picolinic acid pathway

Zhou, Guijuan; Tang, Yiyun; Zuo, Jin-Xi; Tao, Yi; Tang, Jun-Peng; Zhang, Ping; Zou, Wei; Tang, Xiao‐Qing

doi:10.1016/j.bcp.2022.115137

Cited by 4 publications

(5 citation statements)

References 35 publications

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“…While we expected to find a relation between CSF levels of kynurenine pathway metabolites and brain structure volume, only peripheral KYNA/QUIN was correlated with decreases in hippocampal and amygdalar volume. The lack of correlation between central PIC and brain structure volumes is especially surprising as a recent rodent study found that an upregulation of PIC in the hippocampus increases neurogenesis in rodents (Zhou et al, 2022). The discrepancy could be due to a relatively small CSF sample size in the study presented here.…”

Section: Discussioncontrasting

confidence: 59%

Immunological Changes and Brain Function over a Psychotic-Depressive Spectrum

Paul

2023

Linköping University Medical Dissertations

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Section: Discussioncontrasting

confidence: 59%

Immunological Changes and Brain Function over a Psychotic-Depressive Spectrum

Paul

2023

Linköping University Medical Dissertations

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“…Our in vivo results confirmed that DI, a derivative of itaconate, suppresses the microglia-mediated neuroinflammation, thereby alleviating synaptic ultrastructure impairment and ameliorating cognitive deficits induced by chronic T. gondii infection ( Fig 11). Recent studies uncovered that itaconate derivatives can ameliorate the cognitive impairment in the mouse model of AD [76] and alleviate β2-microglobulin-induced cognitive dysfunction [77]. Our previous study also showed that the derivative of itaconate could ameliorate the hippocampus-associated cognitive deficits in T. gondii infected mice [41].…”

Section: Discussionmentioning

confidence: 90%

“…gondii infection ( Fig 11 ). Recent studies uncovered that itaconate derivatives can ameliorate the cognitive impairment in the mouse model of AD [ 76 ] and alleviate β2-microglobulin-induced cognitive dysfunction [ 77 ]. Our previous study also showed that the derivative of itaconate could ameliorate the hippocampus-associated cognitive deficits in T .…”

Section: Discussionmentioning

confidence: 99%

Dimethyl itaconate ameliorates the deficits of goal-directed behavior in Toxoplasma gondii infected mice

et al. 2023

PLoS Negl Trop Dis

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Background The neurotrophic parasite Toxoplasma gondii (T. gondii) has been implicated as a risk factor for neurodegenerative diseases. However, there is only limited information concerning its underlying mechanism and therapeutic strategy. Here, we investigated the effects of T. gondii chronic infection on the goal-directed cognitive behavior in mice. Moreover, we evaluated the preventive and therapeutic effect of dimethyl itaconate on the behavior deficits induced by the parasite. Methods The infection model was established by orally infecting the cysts of T. gondii. Dimethyl itaconate was intraperitoneally administered before or after the infection. Y-maze and temporal order memory (TOM) tests were used to evaluate the prefrontal cortex-dependent behavior performance. Golgi staining, transmission electron microscopy, indirect immunofluorescence, western blot, and RNA sequencing were utilized to determine the pathological changes in the prefrontal cortex of mice. Results We showed that T. gondii infection impaired the prefrontal cortex-dependent goal-directed behavior. The infection significantly downregulated the expression of the genes associated with synaptic transmission, plasticity, and cognitive behavior in the prefrontal cortex of mice. On the contrary, the infection robustly upregulated the expression of activation makers of microglia and astrocytes. In addition, the metabolic phenotype of the prefrontal cortex post infection was characterized by the enhancement of glycolysis and fatty acid oxidation, the blockage of the Krebs cycle, and the disorder of aconitate decarboxylase 1 (ACOD1)-itaconate axis. Notably, the administration of dimethyl itaconate significantly prevented and treated the cognitive impairment induced by T. gondii, which was evidenced by the improvement of behavioral deficits, synaptic ultrastructure lesion and neuroinflammation. Conclusion The present study demonstrates that T. gondii infection induces the deficits of the goal-directed behavior, which is associated with neuroinflammation, the impairment of synaptic ultrastructure, and the metabolic shifts in the prefrontal cortex of mice. Moreover, we report that dimethyl itaconate has the potential to prevent and treat the behavior deficits.

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“…In vitro study shows that 4OI can protect SH-SY5Y cells and epigenetically de-repressed primary neurons from H 2 O 2 [ 61 ]. In vivo experiments have also confirmed that 4OI can alleviate β 2 M-induced cognitive dysfunction and hippocampal neurogenesis impairment [ 62 ]. For the first time, we examined the effects of 4OI as a therapeutic agent for HIE.…”

Section: Discussionmentioning

confidence: 99%

Protecting effects of 4-octyl itaconate on neonatal hypoxic-ischemic encephalopathy via Nrf2 pathway in astrocytes

Yang,

Li,

Yang

et al. 2024

J Neuroinflammation

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Background Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI). Methods We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes. Results We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression. Conclusion Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.

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Itaconate alleviates β2-microglobulin-induced cognitive impairment by enhancing the hippocampal amino-β-carboxymuconate-semialdehyde-decarboxylase/picolinic acid pathway

Cited by 4 publications

References 35 publications

Immunological Changes and Brain Function over a Psychotic-Depressive Spectrum

Immunological Changes and Brain Function over a Psychotic-Depressive Spectrum

Dimethyl itaconate ameliorates the deficits of goal-directed behavior in Toxoplasma gondii infected mice

Protecting effects of 4-octyl itaconate on neonatal hypoxic-ischemic encephalopathy via Nrf2 pathway in astrocytes

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