Curcumin prevents sickness behavior and fever by the modulation of Nrf2 activity in a model of endotoxemia

doi:10.21203/rs.3.rs-879472/v1

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Curcumin prevents sickness behavior and fever by the modulation of Nrf2 activity in a model of endotoxemia

https://doi.org/10.21203/rs.3.rs-879472/v1

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Lipopolysaccharide (LPS) is a potent inducer of inflammation, triggering behavioral changes and fever. The present study aimed to evaluate whether pretreatment with curcumin prevents the behavioral changes and fever induced by LPS through the modulation of nuclear factor-erythroid 2 related factor 2 (Nrf2). Male Wistar rats were pretreated for 2 consecutive days with vehicle or curcumin at doses of 25, 50, or 100 mg/kg by oral gavage. The animals intraperitoneally received either vehicle or LPS at a dose of 500 µg/kg. After 2 h, the behavioral responses were assessed through open field test (OFT), social interaction test, forced swim test (FST), and food intake assessment. The febrile response was assessed by telemetry after vehicle or LPS injection to evaluate the effect of curcumin on the thermoregulatory response during the immunological challenge. The pretreatment with curcumin at doses of 50 and 100 mg/kg prevented the reduction of distance traveled on OFT, increased the immobility time of FST, impaired social withdrawal, decreased food intake, and induced fever. In addition, at these doses, it was possible to observe a significant decrease in the plasma levels of TNF-α and IL1-β and an increase in Nrf2 translocation to the cell nucleus during the immunological challenge. Our data provide further evidence of curcumin's ability to prevent LPS-induced sickness behavior and fever possibly by a mechanism related to the modulation of Nrf2 translocation.

Clinical Pharmacology

cytokines

inflammation

thermoregulation

lipopolysaccharide

polyphenol

sepsis

Communication between the immune system and the brain is important for the host organism to engage in (Sylvia et al., 2018) temporary and specific defense behaviors (Mazuco et al., 2019), such as reduced locomotor and exploratory activities, social withdrawal, anorexia, and anhedonia, which together are known as sickness behavior (Dantzer, 2004; Poon et al., 2015; Nilsson et al., 2017; Oliveira et al., 2020). In addition, inflammation is often accompanied by thermal manifestations, such as fever (Poon et al., 2015; Blomqvist and Engblom, 2018). Although inflammation is an adaptive reaction to different harmful stimuli, in chronic conditions such as sepsis, it can cause severe multiple organ dysfunction and, consequently, neurological disorders and death (Barichello et al., 2019). Therefore, it is important to discover new multi-targeted, non-toxic, and highly potent agents for therapeutic use in different human diseases related to inflammation.

Curcuma longa (curcumin), popularly known as turmeric, has gained considerable attention due to its therapeutic potential for various diseases, owing to its anti-cancer, antioxidant, anti-inflammatory, and neuroprotective properties (Pulido-Moran et al., 2016; Chen et al., 2018; Zhou et al., 2020). In particular, it exerts anti-inflammatory effects through the downregulation of different pro-inflammatory cytokines (Gupta et al., 2014; Kumar et al., 2017) and modulation of transcription factors (Hassan et al., 2019; Zhou et al., 2020), including elevation of the nuclear factor-erythroid 2 related factor 2 (Nrf2) (Hassan et al., 2019). Under physiological conditions, Nrf2 is anchored with the cytoplasmic Kelch-like ECH-associated protein 1 (Keap1), which mediates degradation by ubiquitination (Bellezza et al., 2018; Rahman et al., 2021). In response to stress, Nrf2 dissociates from Keap1 and translocates into the nucleus, where it binds to the antioxidant-response element, regulating the expression of various defensive genes involved in anti-oxidation and anti-inflammation (Bellezza et al., 2018; Rahman et al., 2021; Yang et al., 2021). Therefore, our study aimed to determine whether pretreatment with curcumin attenuates sickness behavior and fever by modulating Nrf2 activity in a model of endotoxemia induced by the systemic administration of lipopolysaccharide (LPS), a cell wall component of gram-negative bacteria.

2.1. Animals

Adult male Wistar rats weighing 200–300 g were obtained from the Central Animal Facility of the Federal University of Alfenas, Brazil. The animals were housed under controlled light (12 h light-dark cycle; lights turned on at 07:00 a.m.) and temperature (22 ± 1°C) conditions with ad libitum access to water and chow. The animals were allowed to habituate to the housing facilities for at least one week before the experiments began. The behavioral studies were performed in a quiet room between 10:00 a.m. and 12:00 p.m. to minimize circadian variation. All experiments were approved by the Ethics Committee of the Federal University of Alfenas and conducted in accordance with their guidelines (protocol #39/2018).

2.2. Behavioral Experimental Protocol

The rats were pretreated with vehicle or curcumin (25, 50, or 100 mg/kg) by oral gavage once a day for 2 consecutive days. One hour after pretreatment on day 2, the control group rats were administered saline (1 ml/kg) or LPS from Escherichia coli (serotype 026:B6; 500 µg/kg) to establish a sickness behavior model (Orlandi et al., 2015). Subsequently, sickness behavior was evaluated by open field test (OFT), forced swim test (FST), social interaction test, or food intake assessment 2 hours after the administration of LPS. This time point was chosen based on previous behavioral, endocrinal, and neurochemical studies (Orlandi et al., 2015; Munshi et al., 2019; Oliveira et al., 2020). LPS was dissolved in a sterile saline solution (0.9% NaCl), and curcumin was suspended in 1% carboxymethylcellulose. LPS and curcumin were purchased from Sigma-Aldrich (São Paulo, Brazil).

Immediately after the behavioral tests, the animals were euthanized, and their blood was collected in heparinized tubes. In addition, their brains were collected, and the mediobasal hypothalami were microdissected for protein expression analysis, as described previously (Enes-Marques et al., 2020). The blood was centrifuged, and the plasma was aliquoted and stored at -20°C. The plasma samples were analyzed for tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) using commercially available enzyme-linked immunosorbent assay kits (PeproTech Funpec-RP, Brazil) according to the manufacturer's guidelines.

For Nrf2 quantification, extraction of cytoplasmic and nuclear proteins from the mediobasal hypothalamus was performed according to the guidelines of the Cytoplasmic and Nuclear Protein Extraction Kit (Boster Biological Technology, Pleasanton, CA, USA). After extraction, the samples were separated and stored in a -80ºC freezer for further analysis.

2.2.1. Open Field Test (OFT)

Locomotor activity was quantified for 5 min in a circular acrylic apparatus (diameter of 60 cm and walls of 50-cm height) with a black background. Each rat (n = 8 per group) was gently placed in the center of the apparatus, and the parameters “distance traveled” and “immobility time” were automatically measured by the software EthoVision XT version 9.0. The apparatus was cleaned with a 5% ethanol solution before the placement of each animal to avoid possible bias effects of odor cues left by previous rats (Orlandi et al., 2015).

2.2.2. Forced Swim Test (FST)

Rats (n = 8 per group) were placed in a vertical acrylic cylinder (diameter × height: 24 × 60 cm) filled with 40 cm of water (25°C). This water volume allowed the animals to swim or float without touching the bottom of the apparatus with their paws or tails. One day before the test, the animals were subjected to 15 min of swimming. After the swimming session, they were dried with towels and placed under a lamp (32°C) for 15–30 min. On the day of the test (24 h after adaptation), the animals were placed in the cylinder for 5 min and their behavior was recorded. The parameters “immobility,” “swimming,” and “climbing” were evaluated. Immobility was considered when the rats made no effort to escape, barring the necessary movements that allowed them to keep their heads above the water (Detke et al., 1997).

2.2.3. Social Interaction Test

Three days before the test, the animals were allowed to individually explore the square open field apparatus (60 × 60-cm wide and 60-cm high) for 15 min/day to familiarize themselves with it, but not with their partner. Each experimental rat was randomly assigned to an unknown partner of the same sex (juvenile visiting rat), with lower age and weight (at least 100 g less). The pair of rats was placed in the apparatus for 10 min, and the total amount of time spent engaging in social interaction (including sniffing, enticing, following, mounting, and crawling on or direct contact with the visiting animal) was recorded (Der-Avakian et al., 2010; Orlandi et al., 2015).

2.2.4. Food Intake

To assess food consumption, the rats (n = 8 per group) were allocated to individual cages with free access to water and chow. On the day of the test, the animals were deprived of chow but not water for 2 h after treatment. After food restriction, the animals were offered previously weighed pelletized chow, and the chow intake pattern was monitored for 24 h by weighing the animals at 2, 4, 6, and 24 h after reintroduction (Rorato et al., 2012).

2.3. Body Temperature Measurement

Animals were anesthetized using 2,2,2-tribromoethanol (Aldrich, Milwaukee, WI, USA; 250 mg/kg, intraperitoneally). A paramedian laparotomy (1.5 cm) was performed to insert a biotelemetry probe device (model G2 E-Mitter®, STARR Life Sciences Corp., Oakmont, PA, USA) into the abdominal cavity. The incision was then sutured, and the implanted device was used for body temperature measurements. Immediately after surgery, the animals were treated with penicillin (100,000 UI). Once fully conscious, the intervened rats were individually housed in cages for 5 days before the experiments for complete recovery. Body temperature was recorded at 10-min intervals for 8 h after the injection of saline or LPS (500 µg/kg, intraperitoneally) in animals previously treated with curcumin (25, 50, or 100 mg/kg) or vehicle for 2 consecutive days. The cages were placed under a telemetry receiver (model ER-4000 Energizer/Receiver Mini-Mitter®, STARR Life Sciences Corp., Oakmont, PA. USA) connected to a personal computer. Data were collected using appropriate software (Vital View®, Mini-Mitter). To determine the basal temperature, the mean temperature measured 30 min before the first administration was calculated, and the difference between the mean basal temperature and the temperature obtained at each interval was calculated to obtain the temperature variation. The temperature response to LPS was monitored during the light phase to minimize activity-related changes in body temperature. Only animals with basal body temperatures below 37.5ºC were subjected to the experimental procedure (Crunfli et al., 2015; Silva and Giusti-Paiva et al., 2015).

2.4. Western Blotting

Aliquots of the lysates containing 30 µg of protein were denatured in Laemmli sample buffer (4% sodium dodecyl sulfate [SDS], 20% glycerol, 0.02% bromophenol blue, Tris 1 M [pH: 6.8], and dithiothreitol 0.1 M) at 95°C for 5 min and subjected to SDS-polyacrylamide gel electrophoresis on a 1.5-mm thick 12% electrophoresis gel. Electrophoresis and subsequent transfer of the proteins to a 0.45-mm nitrocellulose membrane were performed. Subsequently, the membrane was incubated in a 5% skim milk blocking solution with Tris–HCl buffer (1.5 M, pH: 7.4) plus 0.1% Tween 20 (TBS-T) for 2 h. The membranes were incubated overnight with anti-Nrf2 (1:1000, Abcam #ab51163) primary antibodies at 4°C in a solution containing TBS-T. The membranes were then washed and incubated at room temperature for 1 h with a horseradish peroxidase-conjugated anti-mouse-IgG antibody (1:2000, Abcam #ab51163) in a solution containing TBS-T, followed by incubation with a mixture of chemiluminescence reagents (Clarity Western ECL Substrate; Bio-Rad Laboratories, Hercules, CA, USA). Detection by chemiluminescence was perfomed using a ChemiDoc XRS Imaging System (Bio-Rad). Each membrane was stripped and re-probed with anti-β-actin (1:4000; Sigma-Aldrich #A4700) to ensure equal protein loading. Gel digital images were used to quantify optical density. Nfr2 expression was normalized by β-actin and expressed as a percentage of the control group.

2.5. Statistical Analysis

Data were analyzed using GraphPad Prism 8.0. The results are expressed as mean ± standard error of the mean. The symmetry of the data was tested using the Kolmogorov–Smirnov, Shapiro–Wilk, and D'Agostino-Pearson Omnibus normality tests. Data was considered symmetric if approved by at least one of the three tests. The effects of pretreatment (vehicle or curcumin) and immunological challenge factors (treatment with saline or LPS) were analyzed using a two-way analysis of variance followed by Tukey's post-hoc test. The significance level was set at P < 0.05.

Figure 1 shows the effect of oral pretreatment with curcumin at doses of 25, 50, or 100 mg/kg 2 h after LPS-induced inflammation. In the OFT, vehicle + LPS-treated animals presented a reduction in the distance traveled (Fig. 1A) and an increase in the immobility time (Fig. 1B) when compared to the control group. Pretreatment with curcumin at doses of 50 and 100 mg/kg did not significantly change the locomotor activity in the OFT 120 min after intraperitoneal saline injection, but it did prevent the reduction in travel distance (Fig. 1A) and immobility time (Fig. 1B) induced by LPS, reaching the same levels exhibited by the control group. The total social interaction time in animals immunologically challenged by LPS was significantly reduced when compared to the control group (Fig. 1C). Pretreatment with curcumin at 50 or 100 mg/kg prevented the reduction of social behavior induced by LPS (Fig. 1C). Regarding feeding behavior, the animals treated with LPS presented a reduction in food intake 24 h after injection when compared to the control group. However, when pretreated with curcumin at 50 or 100 mg/kg, the animals presented an increase in the feeding pattern after 24 h when compared to animals treated with vehicle + LPS (Fig. 1D). Pretreatment with curcumin at 25 mg/kg did not prevent the decrease in locomotor activity (Fig. 1A and 1B), social interaction (Fig. 1C), or hypophagia (Fig. 1D) induced by LPS.

The analysis of the FST revealed that the immunological challenge caused by LPS increased the immobility time (Fig. 2A) and reduced the swimming (Fig. 2B) and climbing times (Fig. 2C) when compared to the control group. Similar to the OFT results, pretreatment with curcumin at 25 mg/kg did not prevent the increase in immobility time (Fig. 2A) and, consequently, did not prevent the reduction in swimming time (Fig. 2B) induced by LPS. Only pretreatments with curcumin at 50 or 100 mg/kg were able to change the immobility and swimming times (Fig. 2A and 2B), that is, only at these doses, curcumin was able to prevent depressive-like behavior. Regarding climbing, we observed a significant difference only in animals pretreated with curcumin at 100 mg/kg when compared to the vehicle + LPS-treated group (i.e., these animals presented an increase in climbing time; Fig. 2C).

Figure 3A shows that animals in the vehicle + LPS-treated group developed a febrile response after LPS injection when compared to the control group. The thermal index (area under the curve, Fig. 3B) from 2 to 8 h after LPS, observed in rats pretreated with curcumin at 25 mg/kg, was not able to prevent fever; however, pretreatment with curcumin at 50 or 100 mg/kg prevented the LPS-induced increase in body temperature.

Plasma levels of TNF-α (Fig. 4A) and IL1-β (Fig. 4B) significantly increased 2 h after LPS injection. Pretreatment with curcumin at all tested doses prevented the increase in TNF-α and IL1-β when compared to the vehicle + LPS-treated group. Since the well-established activation pattern of Nrf2 is a translocation from the cytoplasm to the nucleus, we investigated the cytoplasmic and nuclear Nrf2. The results showed that when compared to the vehicle group, curcumin reduced cytoplasmic Nrf2 and increased nuclear Nrf2 with both saline and LPS treatment, suggesting that curcumin administration induced Nrf2 nuclear translocation. The statistical data are presented in Table 1.

Table 1

Two-way analysis of variance in groups pretreated with vehicle or curcumin (pretreatment factor) and subjected to an injection of vehicle or LPS (immunological challenge factor) in the open field test, social interaction test, food intake assessment, forced swim test, body temperature measurement (thermal index), plasma cytokine measurements, and Nrf2 expression on hypothalamus.
Parameters	Pretreatment factor	Immunological challenge factor	Interaction
Open field test
Distance traveled	F_(3,56) = 4.77, P < 0.01	F_(1,56) = 37.6, P < 0.001	F_(3,56) = 6.17, P < 0.01
Immobility time	F_(3,56) = 3.24, P < 0.05	F_(1,56) = 38.1, P < 0.001	F_(3,56) = 5.31, P < 0.01
Social interaction test
Interaction time	F_(3,56) = 20.8, P < 0.001	F_(1,56) = 167, P < 0.001	F_(3,56) = 34.7, P < 0.001
Food ingestion
Food intake	F_(3,56) = 25.5, P < 0.001	F_(1,56) = 140, P < 0.001	F_(3,56) = 26.4, P < 0.001
Forced swim test
Floating time	F_(3,56) = 14.7, P < 0.001	F_(1,56) = 21.0, P < 0.001	F_(3,56) = 6.08, P < 0.01
Swimming time	F_(3,56) = 6.85, P < 0.001	F_(1,56) = 15.3; P < 0.001	F_(3,56) = 4.65, P < 0.01
Climbing time	F_(3,56) = 19.6; P < 0.001	F_(1,56) = 3.69, P = 0.060	F_(3,56) = 8.36, P < 0.05
Body temperature
Thermal index	F_(3,43) = 18.8, P < 0.001	F_(1,43) = 33.5, P < 0.001	F_(3,53) = 14.6, P < 0.001
Cytokines
TNF-α	F_(2,40) = 16.7; P < 0.001	F_(1,40) = 26.0; P < 0.001	F_(2,40) = 16.8, P < 0.001
IL-1β	F_(2,40) = 15.4, P < 0.001	F_(1,40) = 25.3, P < 0.001	F_(2,40) = 15,9, P < 0.001
Nrf2 expression
Cytoplasmic Nrf2	F_(2,25) = 4.05, P < 0.05	F_(1,25) = 10.9, P < 0.01	F_(2,25) = 0.33, P = 0.720
Nuclear Nrf2	F_(2,25) = 3.65, P < 0.05	F_(1,25) = 3.99, P = 0.056	F_(2,25) = 0.05, P = 0.945
F: F value; P: P value; TNF-α: tumor necrosis factor-α; IL1-β: interleukin1-β; Nrf2: nuclear factor-erythroid 2 related factor 2

In our study, LPS induced a decrease in exploratory behavior in rats in OFT, depressive-like symptoms in FST, social interaction, and anorexia, allowing us to verify the ability of this endotoxin to produce characteristic sickness behavior. Sickness behavior accompanied by fever constitute a highly regulated and adaptive strategy to fight infections (Quan and Banks, 2007; Harden et al., 2015; Oliveira et al., 2020). Our results show that curcumin, when administered prior to an immunological challenge, may counteract a loss of motivated behaviors and fever during illness, suggesting a potential effect of curcumin in modulating sickness behavior.

LPS is recognized by CD14–MD2 receptors present in monocyte membranes, and it sends intracellular signals via toll-like receptor 4 (TLR-4), culminating in the activation of NF-kB and release of pro-inflammatory mediators (Engblom et al., 2002; Bellezza et al., 2018; Blomqvist and Engblom, 2018). The production of TNF-α and IL1-β induces the synthesis of cyclooxygenase enzyme-2 (COX-2) in the hypothalamic vascular network, resulting in an increase in the cerebral levels of prostaglandin E2 via COX-2 (Engblom et al., 2002; Kawahara et al., 2015; Blomqvist and Engblom, 2018), sickness behavior (Dantzer, 2004; de Paiva et al., 2010; Oliveira et al., 2020), and onset of LPS-induced fever (Evans et al., 2015; Garami et al., 2018).

Intracerebroventricular and intraperitoneal administration of pro-inflammatory cytokines induces a complete sickness state in rodents, manifested by a reduction in locomotor/exploratory behavior and food intake, and an increase in immobility time, anhedonia, social withdrawal, and fever (Dantzer, 2004; Palin et al., 2007; de Paiva et al., 2010). In our study, we evaluated the plasma levels of cytokines to investigate the mechanisms responsible for the effects of curcumin on the prevention of sickness behavior and fever. We observed that pretreatment with curcumin prevented the peripheral synthesis of TNF-α and IL-1β 2 h after the immunological challenge with LPS. Previous studies have shown that curcumin negatively regulates the synthesis of different cytokines by competitively binding to myeloid differentiation protein 2, which is the LPS-binding component of the MD-2/TRL4 complex (Mohan and Gupta, 2018). In addition, curcumin also has the ability to modulate LPS-induced TLR-4 receptor signaling by inhibiting MyD88-dependent pathways and TRIF proteins (Wang et al., 2015; Boozari et al., 2019).

In vivo studies have shown that the transcription factor Nrf2 plays an important role in neuroinflammatory response (Nedzvetsky et al., 2017; Rahman et al., 2021). Under basal conditions, Nrf2 is bound to its repressive protein Keap1 in the cytoplasm and is degraded through the ubiquitin-proteasome pathway. However, exposure to stressors and inducers, such as cytokines, releases Nrf2 from Keap1 and, consequently, induces its translocation to the nucleus of the cell, culminating in the expression of cytoprotective genes (Mohan and Gupta, 2018; Rojo et al., 2018; Rahman et al., 2021). In our study, we explored the possible effects of curcumin on Nrf2 translocation during endotoxemia. The pretreatment with 50 or 100 mg/kg of curcumin induced a higher dose-dependent increase in Nrf2 translocation 2 h after LPS administration. As for the effect of curcumin on Nrf2 activity, it has been demonstrated that this compound exerts an exogenous agonist action on Nrf2 (Liu et al., 2016).

In conclusion, our data indicate that pretreatment with curcumin prevents the LPS-induced inflammatory response and, consequently, sickness behavior and fever. The present study suggests that curcumin is a potential substance capable of preventing or reducing systemic inflammation by modulating the translocation of Nrf2.

Credit authorship contribution statement

Dr. L. Reis was involved in the study conception and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Dr. M.K. Oliveira, Dr. V.C.T. Rojas, Dr. T.H. Batista, Dr. E.S. Estevam, and Dr. F. Vitor-Vieira were involved in the study conception and design, acquisition of data, and analysis and interpretation of data. Dr. F.C. Vilela and Dr. A. Giusti-Paiva were involved in the study conception and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; administrative, technical, or material support; and study supervision.

FST

forced swim test

IL-1β

interleukin-1β

Keap1

Kelch-like ECH-associated protein 1

LPS

Lipopolysaccharide

Nrf2

nuclear factor-erythroid 2 related factor 2

OFT

open field test

TNF-α

tumor necrosis factor-α

Funding

This work was supported by Fundação de Amparo a Pesquisa de Minas Gerais (FAPEMIG #03346-18, AG-P) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, #308762/2017-7, AG-P; #429035/2018-7, FCV; and #311709/2018-4, FCV). The FAPEMIG and CNPq had no further role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the report; or the decision to submit the paper for publication.

Availability of data and materials

This study's data are included in the article, and the corresponding author can provide the primary data.

Consent to participate

All authors are aware of their participation in this work.

Consent for publication

All authors are aware of the publication of this work.

Declaration of competing interest

The authors report no biomedical financial interests or other potential conflicts of interest.

Code availability

Not applicable.

Acknowledgements

We are grateful to José dos Reis Pereira for his excellent technical support.

Barichello T, Sayana P, Giridharan VV, Arumanayagam AS, Narendran B, Della Giustina A, Petronilho F, Quevedo J, Dal-Pizzol F (2019) Long-Term Cognitive Outcomes After Sepsis: a Translational Systematic Review. Mol Neurobiol 56(1):186–251. https://doi.org/10.1007/s12035-018-1048-2
Bellezza I, Giambanco I, Minelli A, Donato R (2018) Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res 1865(5):721–733. https://doi.org/10.1016/j.bbamcr.2018.02.010
Blomqvist A, Engblom D (2018) Neural Mechanisms of Inflammation-Induced Fever. Neuroscientist 24(4):381–399. https://doi.org/10.1177/1073858418760481
Boozari M, Butler AE, Sahebkar A (2019) Impact of curcumin on toll-like receptors. J Cell Physiol 234(8):12471–12482. https://doi.org/10.1002/jcp.28103
Chen L, Lu Y, Zhao L, Hu L, Qiu Q, Zhang Z, Li M, Hong G, Wu B, Zhao G, Lu Z (2018) Curcumin attenuates sepsis-induced acute organ dysfunction by preventing inflammation and enhancing the suppressive function of Tregs. Int Immunopharmacol 61:1–7. https://doi.org/10.1016/j.intimp.2018.04.041
Crunfli F, Vilela FC, Giusti-Paiva A (2015) Cannabinoid CB1 receptors mediate the effects of dipyrone. Clin Exp Pharmacol Physiol 42(3):246–255. https://doi.org/10.1111/1440-1681.12347
Dantzer R (2004) Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol 500(1–3):399–411. https://doi.org/10.1016/j.ejphar.2004.07.040
de Paiva VN, Lima SN, Fernandes MM, Soncini R, Andrade CA, Giusti-Paiva A (2010) Prostaglandins mediate depressive-like behaviour induced by endotoxin in mice. Behav Brain Res 215(1):146–151. https://doi.org/10.1016/j.bbr.2010.07.015
Der-Avakian A, Markou A (2010) Withdrawal from chronic exposure to amphetamine, but not nicotine, leads to an immediate and enduring deficit in motivated behavior without affecting social interaction in rats. Behav Pharmacol 21(4):359–368. https://doi.org/10.1097/FBP.0b013e32833c7cc8
Detke MJ, Johnson J, Lucki I (1997) Acute and chronic antidepressant drug treatment in the rat forced swimming test model of depression. Exp Clin Psychopharmacol 5(2):107–112. https://doi.org/ 10.1037//1064-1297.5.2.107
Enes-Marques S, Rojas VCT, Batista TH, Vitor-Vieira F, Novais CO, Vilela FC, Rafacho A, Giusti-Paiva A (2020) Neonatal overnutrition programming impairs cholecystokinin effects in adultmale rats. J Nutr Biochem 86:108494. https://doi.org/10.1016/j.jnutbio.2020.108494
Engblom D, Ek M, Saha S, Ericsson-Dahlstrand A, Jakobsson PJ, Blomqvist A (2002) Prostaglandins as inflammatory messengers across the blood-brain barrier. J Mol Med (Berl) 80(1):5–15. https://doi.org/10.1007/s00109-001-0289-z
Evans SS, Repasky EA, Fisher DT (2015) Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol 15(6):335–349. https://doi.org/10.1038/nri3843
Garami A, Steiner AA, Romanovsky AA (2018) Fever and hypothermia in systemic inflammation. Handb Clin Neurol 157:565–597. https://doi.org/10.1016/B978-0-444-64074-1.00034-3
Gupta SC, Tyagi AK, Deshmukh-Taskar P, Hinojosa M, Prasad S, Aggarwal BB (2014) Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys 559:91–99. https://doi.org/10.1016/j.abb.2014.06.006
Harden LM, Kent S, Pittman QJ, Roth J (2015) Fever and sickness behavior: Friend or foe? Brain Behav Immun 50:322–333. https://doi.org/10.1016/j.bbi.2015.07.012
Hassan FU, Rehman MS, Khan MS, Ali MA, Javed A, Nawaz A, Yang C (2019) Curcumin as an Alternative Epigenetic Modulator: Mechanism of Action and Potential Effects. Front Genet 10:514. https://doi.org/10.3389/fgene.2019.00514
Kawahara K, Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y (2015) Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors. Biochim Biophys Acta 1851(4):414–421. https://doi.org/10.1016/j.bbalip.2014.07.008
Kumar P, Sulakhiya K, Barua CC, Mundhe N (2017) TNF-α, IL-6 and IL-10 expressions, responsible for disparity in action of curcumin against cisplatin-induced nephrotoxicity in rats. Mol Cell Biochem 431(1–2):113–122. https://doi.org/10.1007/s11010-017-2981-5
Liu Z, Dou W, Zheng Y, Wen Q, Qin M, Wang X, Tang H, Zhang R, Lv D, Wang J, Zhao S (2016) Curcumin upregulates Nrf2 nuclear translocation and protects rat hepatic stellate cells against oxidative stress. Mol Med Rep 13(2):1717–1724. https://doi.org/10.3892/mmr.2015.4690
Mazuco TRR, Biondi TF, Silva EP, Bernardi MM, Kirsten TB (2019) LPS-induced sickness behavior is not affected by selenium but is switched off by psychogenic stress in rats. Vet Res Commun 43(4):239–247. https://doi.org/10.1007/s11259-019-09766-8
Mohan S, Gupta D (2018) Crosstalk of toll-like receptors signaling and Nrf2 pathway for regulation of inflammation. Biomed Pharmacother 108:1866–1878. https://doi.org/10.1016/j.biopha.2018.10.019
Munshi S, Parrilli V, Rosenkranz JA (2019) Peripheral anti-inflammatory cytokine Interleukin-10 treatment mitigates interleukin-1β - induced anxiety and sickness behaviors in adult male rats. Behav Brain Res 372:112024. https://doi.org/10.1016/j.bbr.2019.112024
Nedzvetsky VS, Agca CA, Kyrychenko SV (2017) Neuroprotective Effect of Curcumin on LPS-enabled Astrocytes Is Related to the Prevention of GFAP and NF-ΚB upregulation. Neurophysiol 49:305–307. https://doi.org/10.1007/s11062-017-9687-x
Nilsson A, Wilhelms DB, Mirrasekhian E, Jaarola M, Blomqvist A, Engblom D (2017) Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent. Brain Behav Immun 61:236–243. https://doi.org/10.1016/j.bbi.2016.12.007
Oliveira MK, Dos Santos RS, Cabral LDM, Vilela FC, Giusti-Paiva A (2020) Simvastatin attenuated sickness behavior and fever in a murine model of endotoxemia. Life Sci 254:117701. https://doi.org/10.1016/j.lfs.2020.117701
Orlandi L, Fonseca WF, Enes-Marques S, Paffaro VA Jr, Vilela FC, Giusti-Paiva A (2015) Sickness behavior is accentuated in rats with metabolic disorders induced by a fructose diet. J Neuroimmunol 289:75–83. https://doi.org/10.1016/j.jneuroim.2015.10.014
Palin K, Bluthé RM, McCusker RH, Moos F, Dantzer R, Kelley KW (2007) TNFalpha-induced sickness behavior in mice with functional 55 kD TNF receptors is blocked by central IGF-I. J Neuroimmunol 187(1–2):55–60. https://doi.org/10.1016/j.jneuroim.2007.04.011
Poon DC, Ho YS, Chiu K, Wong HL, Chang RC (2015) Sickness: From the focus on cytokines, prostaglandins, and complement factors to the perspectives of neurons. Neurosci Biobehav Rev 57:30–45. https://doi.org/10.1016/j.neubiorev.2015.07.015
Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M (2016) Curcumin and Health. Molecules 21(3):264. https://doi.org/10.3390/molecules21030264
Quan N, Banks WA (2007) Brain-immune communication pathways. Brain Behav Immun 21(6):727–735. https://doi.org/10.1016/j.bbi.2007.05.005
Rahman S, Mathew S, Nair P, Ramadan WS, Vazhappilly CG (2021) Health benefits of cyanidin-3-glucoside as a potent modulator of Nrf2-mediated oxidative stress. Inflammopharmacology 29(4):907–923. https://doi.org/10.1007/s10787-021-00799-7
Rojo AI, Pajares M, García-Yagüe AJ, Buendia I, Van Leuven F, Yamamoto M, López MG, Cuadrado A (2018) Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy. Redox Biol 18:173–180. https://doi.org/10.1016/j.redox.2018.07.006
Rorato R, Reis WL, de Carvalho Borges B, Antunes-Rodrigues J, Elias LL (2012) Cannabinoid CBâ࿽࿽ receptor restrains accentuated activity of hypothalamic corticotropin-releasing factor and brainstem tyrosine hydroxylase neurons in endotoxemia-induced hypophagia in rats. Neuropharmacology 63(1):154–160. https://doi.org/10.1016/j.neuropharm.2011.11.009
Silva VC, Giusti-Paiva A (2015) Sickness behavior is delayed in hypothyroid mice. Brain Behav Immun 45:109–117. https://doi.org/10.1016/j.bbi.2014.12.014
Sylvia KE, Demas GE (2018) A gut feeling: Microbiome-brain-immune interactions modulate social and affective behaviors. Horm Behav 99:41–49. https://doi.org/10.1016/j.yhbeh.2018.02.001
Wang Y, Shan X, Dai Y, Jiang L, Chen G, Zhang Y, Wang Z, Dong L, Wu J, Guo G, Liang G (2015) Curcumin Analog L48H37 Prevents Lipopolysaccharide-Induced TLR4 Signaling Pathway Activation and Sepsis via Targeting MD2. J Pharmacol Exp Ther 353(3):539–550. https://doi.org/10.1124/jpet.115.222570
Yang Y, Sheng Q, Nie Z, Liu L, Zhang W, Chen G, Ye F, Shi L, Lv Z, Xie J, Wang D (2021) Daphnetin inhibits spinal glial activation via Nrf2/HO-1/NF-κB signaling pathway and attenuates CFA-induced inflammatory pain. Int Immunopharmacol 98:107882. https://doi.org/10.1016/j.intimp.2021.107882
Zhou T, Wang Y, Liu M, Huang Y, Shi J, Dong N, Xu K (2020) Curcumin inhibits calcification of human aortic valve interstitial cells by interfering NF-κB, AKT, and ERK pathways. Phytother Res 34(8):2074–2081. https://doi.org/10.1002/ptr.6674

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Curcumin prevents sickness behavior and fever by the modulation of Nrf2 activity in a model of endotoxemia

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Abstract

Figures

1. Introduction

2. Methods

2.1. Animals

2.2. Behavioral Experimental Protocol

2.2.1. Open Field Test (OFT)

2.2.2. Forced Swim Test (FST)

2.2.3. Social Interaction Test

2.2.4. Food Intake

2.3. Body Temperature Measurement

2.4. Western Blotting

2.5. Statistical Analysis

3. Results

4. Discussion

Abbreviations

Declarations

References

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