Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration

Abstract Objectives Curcumin, extracted from the rhizome Curcuma longa, has been shown to be beneficial for neuroprotection in previous studies. In a recent study, a novel formulation of curcumin resulted in an increased relative absorption by 46 times (CurcuWIN®) of the total curcuminoids over the unformulated standard curcumin form. However, the exact mechanisms by which curcumin demonstrates its neuroprotective effects are not fully understood. The present study aimed to investigate the effects of curcumin supplementation on the expression of brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), a main component of the glial scar, and growth-associated protein-43 (GAP-43), a signaling molecule in traumatic brain injury (TBI). Methods Brain injury was induced using a cold trauma model in male mice that were treated with curcumin (50 mg/kg) or vehicle via intraperitoneal administration just after TBI. Mice were divided into two groups: TBI + vehicle group and TBI + curcumin (CurcuWIN) group. Results The results show that curcumin treatment reduced the infarct volume in the brain. TBI induction increased inflammatory cytokines (IL-1β and IL-6), nuclear factor-κB (NF-κB) and GFAP, and reduced BDNF, GAP-43, neural cell adhesion molecule (ICAM) and nuclear factor erythroid 2-related factor 2 (Nrf2) levels in the brain. Interestingly, curcumin decreased the levels of NF-κB, IL-1β, IL-6, and GFAP, and increased BDNF, GAP-43, ICAM and Nrf2 levels in the brain. Conclusions In conclusion, these results showed that curcumin could increase the levels of BDNF, GAP-43, ICAM, and Nrf2 and attenuate brain injury in the model of TBI. Funding Sources This study was supported by OmniActive Health Technologies Inc. (NJ, USA). This work was also supported in part by the Turkish Academy of Sciences. Supporting Tables, Images and/or Graphs

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Astaxanthin Activates Nuclear Factor Erythroid-Related Factor 2 and the Antioxidant Responsive Element (Nrf2-ARE) Pathway in the Brain after Subarachnoid Hemorrhage in Rats and Attenuates Early Brain Injury

Marine Drugs ◽

10.3390/md12126125 ◽

2014 ◽

Vol 12 (12) ◽

pp. 6125-6141 ◽

Cited By ~ 60

Author(s):

Qi Wu ◽

Xiang-Sheng Zhang ◽

Han-Dong Wang ◽

Xin Zhang ◽

Qing Yu ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Early Brain Injury ◽

Related Factor ◽

Nuclear Factor ◽

Responsive Element ◽

The Brain ◽

Antioxidant Responsive Element

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Catalase Overexpression Prevents Nuclear Factor Erythroid 2-Related Factor 2 Stimulation of Renal Angiotensinogen Gene Expression, Hypertension, and Kidney Injury in Diabetic Mice

Diabetes ◽

10.2337/db13-1830 ◽

2014 ◽

Vol 63 (10) ◽

pp. 3483-3496 ◽

Cited By ~ 27

Author(s):

S. Abdo ◽

Y. Shi ◽

A. Otoukesh ◽

A. Ghosh ◽

C.-S. Lo ◽

...

Keyword(s):

Gene Expression ◽

Kidney Injury ◽

Related Factor ◽

Nuclear Factor ◽

Diabetic Mice ◽

Angiotensinogen Gene ◽

Stimulation Of

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Inhibition of microglial β-glucocerebrosidase hampers the microglia-mediated antioxidant and protective response in neurons

Journal of Neuroinflammation ◽

10.1186/s12974-021-02272-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Electra Brunialti ◽

Alessandro Villa ◽

Marianna Mekhaeil ◽

Federica Mornata ◽

Elisabetta Vegeto ◽

...

Keyword(s):

Morphological Changes ◽

Neuronal Response ◽

Related Factor ◽

Nuclear Factor ◽

Gaucher's Disease ◽

Gaucher’S Disease ◽

Reporter Mice ◽

Microglial Phenotype ◽

Increased Risk ◽

The Brain

Abstract Background Homozygotic mutations in the GBA gene cause Gaucher’s disease; moreover, both patients and heterozygotic carriers have been associated with 20- to 30-fold increased risk of developing Parkinson’s disease. In homozygosis, these mutations impair the activity of β-glucocerebrosidase, the enzyme encoded by GBA, and generate a lysosomal disorder in macrophages, which changes morphology towards an engorged phenotype, considered the hallmark of Gaucher’s disease. Notwithstanding the key role of macrophages in this disease, most of the effects in the brain have been attributed to the β-glucocerebrosidase deficit in neurons, while a microglial phenotype for these mutations has never been reported. Methods We applied the bioluminescence imaging technology, immunohistochemistry and gene expression analysis to investigate the consequences of microglial β-glucocerebrosidase inhibition in the brain of reporter mice, in primary neuron/microglia cocultures and in cell lines. The use of primary cells from reporter mice allowed for the first time, to discriminate in cocultures neuronal from microglial responses consequent to the β-glucocerebrosidase inhibition; results were finally confirmed by pharmacological depletion of microglia from the brain of mice. Results Our data demonstrate the existence of a novel neuroprotective mechanism mediated by a direct microglia-to-neuron contact supported by functional actin structures. This cellular contact stimulates the nuclear factor erythroid 2-related factor 2 activity in neurons, a key signal involved in drug detoxification, redox balance, metabolism, autophagy, lysosomal biogenesis, mitochondrial dysfunctions, and neuroinflammation. The central role played by microglia in this neuronal response in vivo was proven by depletion of the lineage in the brain of reporter mice. Pharmacological inhibition of microglial β-glucocerebrosidase was proven to induce morphological changes, to turn on an anti-inflammatory/repairing pathway, and to hinder the microglia ability to activate the nuclear factor erythroid 2-related factor 2 response, thus increasing the neuronal susceptibility to neurotoxins. Conclusion This mechanism provides a possible explanation for the increased risk of neurodegeneration observed in carriers of GBA mutations and suggest novel therapeutic strategies designed to revert the microglial phenotype associated with β-glucocerebrosidase inhibition, aimed at resetting the protective microglia-to-neuron communication.

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