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Nano-Curcumin improves caffeine-induced cerebral alterations in male Wistar rats by modifying oxidative stress, inflammation, and COX-2/NF-κB/Nrf2 signaling

Beni-Suef University Journal of Basic and Applied Sciences volume 13, Article number: 93 (2024) Cite this article

Abstract

Background

This research aims to determine the probable protective effect of nano-curcumin (N-CUR) on caffeine (1,3,7-trimethylxanthine)-induced neurotoxicity in cerebral rats.

Methods

Twenty-four male Wistar rats were divided into three groups: control, caffeine (150 mg kg−1), and caffeine (150 mg kg−1) treated with N-CUR (300 mg kg−1). All treatments were administrated by gavage every day for a month.

Results

Administration of caffeine significantly elevated the levels of serum interleukins 6 (IL-6), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), and cyclooxygenase2 (COX-2). Also, there was a significant increase in levels of cerebral malondialdehyde (MDA), significantly diminished glutathione (GSH), and superoxide dismutase (SOD) activity. Caffeine administration significantly downregulated the gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB). Administration of N-CUR caused a significant amelioration in TNF-α and IL-6 levels and a significant rise in SOD activity, while it caused a significant downregulation in NF-κB mRNA expression. Additionally, N-CUR has exerted insignificant amelioration of COX-2 and MDA contents and Nrf2 mRNA expression compared to the caffeine-treated group.

Conclusion

N-CUR may have a mild to moderate ameliorative effect on caffeine-induced apoptosis, oxidative stress, and inflammatory response in the cerebrum.

Highlights

  • Caffeine induced oxidative stress, apoptosis, and inflammation in the cerebrum.

  • Caffeine resulted in significantly increased COX-2 and VEGF levels.

  • Caffeine increased the expression of NF-ĸB and inhibited Nrf2 in cerebrum.

  • N-CUR may have a mild to moderate ameliorative effect on caffeine exposure.

  • Humans could confine caffeine intake to evade any alterations in the cerebrum.

AbstractSection Graphical abstract

1 Background

Caffeine (1,3,7-trimethylxanthine) is a methylxanthine central nervous system (CNS) stimulant [7, 35, 47, 95], the most widely consumed psychoactive drug [2, 67,68,69] and one of the most researched food components [50, 57], affecting the metabolic mechanisms [83]. Most people consume caffeine in drinks because it can be used in medical products such as analgesics, diuretics, muscle relaxants, and headache medications [45]. It is also used as a pain reliever in flu and cold treatments. Additionally, it has been discovered that Parkinsonism’s motor symptoms and neuronal loss are slowed down by caffeine. [12]. Notably, moderate consumption of caffeine lowers mortality risk and metabolic disorders, and this action may be attributed to its ergogenic action [98]. Excessive caffeine consumption harms the body through significant toxic effects [88], including the symptoms of a colonic stimulant [58], anxiousness, delirium, headache, dehydration, insomnia, nervousness, hyperglycemia, and arrhythmia [66]. Also, the initiation of apoptosis and cell death [34], modulation of inflammatory actions [33], and low birth weight [82] were reported. High doses of caffeine intake may decrease neurogenesis in the cerebral cortex and subventricular zone (SVZ) [22] and elevate apoptosis across the cerebral hemisphere [10]. These pathological alterations might be attributed to oxidative stress (egress of malondialdehyde, MDA) [48]. Caffeine exposure decreases the levels of vascular endothelial growth factor (VEGF) [55], interleukin 1 beta (IL-1β) [56], IL-6 and tumor necrosis factor-alpha (TNF-α) [92]. In vitro, Chavez-Valdez et al. recorded that the addition of 10 mg caffeine/ml decreased the production of TNF-α [14]. Interestingly, caffeine can control cytokine production and immunity [33]. Its half-life is 5 or 6 h after digestion [33].

Curcumin (CUR, diferuloylmethane), turmeric’s (Curcuma longa) active component, is a hydrophobic polyphenolic compound [5, 25] that is safe for both humans and animals and has chemo-preventive properties [6, 79]. Furthermore, CUR has positive effects in several clinical cases, like cancer in the esophagus, colon, skin, and breast [32, 71], liver injury [40], and experimental brain toxicity [61]. It is also used to cure a variety of mild to moderate human diseases in traditional medicine in Asia and Africa, such as liver, lungs, gastrointestinal, and muscular systems, as well as aches and pains abnormalities [41]. CUR is an effective anti-inflammatory, anticancer, and antioxidant and modulates several cellular signal transduction pathways [5, 49, 78]. Despite its medicinal benefits, CUR is difficult to dissolve in water and is particularly sensitive to physiological pH fluctuations [44]. It also has a low absorption rate in the gastrointestinal system in acidic conditions [91]. As a result, methods for increasing the solubility of functional herbal components with low water solubility and protecting them until they get to their target site in the body are useful [91]. Some of the techniques that have been used for increasing the solubility of CUR include CUR liposomalization, CUR phospholipid complexing, CUR nanoformulation, and CUR nanoencapsulation [19].

Nano-curcumin (N-CUR) has the same activity as CUR but with higher stability and solubility [25]. N-CUR can profoundly enhance cell permeability and protection in vivo and in vitro [75]. Additionally, glutamate content in cerebrospinal fluid decreases because N-CUR enhances glutamate transporter-1 after subarachnoid hemorrhage and prevents microglia from being reactivated [96]. We used nanoparticles to elevate the bioavailability of CUR [15] and to prolong its retention time in the brain [87]. Additionally, Sarawi et al. stated that N-CUR's neuroprotection is more effective than curcumin's [61, 75]. It can reduce blood–brain barrier dysfunction following subarachnoid hemorrhage and prevent tight junction protein destruction [96]. N-CUR is more promising in dry eye syndrome [38] and fighting cancer [5]. Our study's objective was to assess the possible protective impact of N-CUR on caffeine-induced alterations in the cerebrum of male albino rats through histopathological, biochemical, and qRT-PCR studies.

2 Methods

2.1 Chemicals

Caffeine anhydrous (1,3,7-trimethylxanthine) was purchased from SD Fine-India Company, and N-CUR powder was purchased from National Nanotech Company. Caffeine and N-CUR powder were stored at 2–4 °C. The purest chemicals and reagents were used in this experiment.

2.2 Experimental animals

Twenty-four adult Wistar rats (Rattus norvegicus) weighing 170–190 gm were received from the National Research Center. To exclude any concurrent infections and to adapt to the new circumstances, adult rats were kept in the department animal house for 14 days. All animals were sheltered in cages with six rats each at a normal room temperature and light/dark cycle. Standard pellet food and unlimited access to sterile water were provided for the animals. Each effort was made in order to decrease the use of animals and their pain.

Each animal used was conducted under a protocol that has been approved by BSU-IACUC with the permit number: 021–148.

2.3 Experimental design

Rats were assigned in a random way to three groups (n = 6 rats per group), and the treatment was administered every day for a month as the following:

Group I (control group): Animals were used as vehicle controls that only received sterilized distilled water.

Group II (caffeine group): Animals were administered 150 mg caffeine/kg b.wt./day (dissolved in sterile D.W.) orally by gastric tubing.The dose was selected according to the publication of [7]. Notably, the mode of administration was different.

Group III (caffeine + N-CUR): Animals that administrated a daily dose of 150 mg caffeine were treated orally with N-CUR at a dose of 300 mg/kg b. wt/day [97].

2.4 Collecting blood and tissue samples

Anesthetized animals were euthanized soon after the thirty-day time frame was completed, and blood was extracted by ventricular puncturing. Clotting blood samples were centrifuged at 3000 rpm for 20 min (1006.2g) to obtain the serum. Then, this serum was stored at − 20° C for further biochemical evaluation. Each rat's cerebrum was removed and separated into three sections. Using a Teflon homogenizer, the first portion was homogenized with 10% (w/v) cold phosphate-buffered saline (PBS), centrifuged at 1000 g for ten minutes, and we stored the pure supernatant at − 20°C. For RNA isolation, the second fraction was stored in a frozen condition at − 70 °C. The third cerebral part was maintained in 10% neutral buffered formalin (NBF).

2.5 Histological examination

Cerebral tissues were quickly fixed for one day in 10% NBF, then cleared in xylene, embedded in paraffin wax, blocked, serially sectioned, and stained with H&E stain. Zeiss binocular microscope with an ocular image acquisition software and Q Imaging digital camera was used to examine the slides.

2.6 ELISA assays

Serum (6 samples/6 rats/parameter/group) was used to determine the concentrations of the following:

2.6.1 Estimation of cyclooxgynase2 (COX-2)

COX-2 kit was purchased from Millipore ELISA Kit, USA, Cat No. CBA053. Rat anti-PTGS2/COX-2 antibodies were coated on the surface of ELISA microplates. Following the addition of samples or standards, each well received a sequential addition of an Avidin-Horseradish Peroxidase (HRP) mixture and a biotinylated detection antibody, especially for Rat PTGS2/COX-2. At a wavelength of 450 nm, the optical density of PTGS2/COX-2 coupled with the biotinylated detection antibody was determined spectrophotometrically.

2.6.2 Estimation of interleukins IL-6 level

The IL-6 level was assayed by utilizing an ELISA kit purchased from MyBioSource (USA), Cat No. MBS355410. Rat anti-IL-6 antibodies were coated on the surface of ELISA microplates. Following the addition of samples or standards, each well received HRP conjugate and an IL-6 biotinylated specific antibody before being incubated. At a wavelength of 450 nm, the optical density of IL-6 coupled with the biotinylated detection antibody was determined spectrophotometrically.

2.6.3 Estimation of tumor necrosis factor-alpha (TNF-α)

The level of TNF-α was assayed by using a rat ELISA kit purchased from RayBio®, Cat No. ELR-TNF-α. Rat anti-TNF-α antibodies were coated on the ELISA microplate. Following the addition of samples or standards, each well received HRP conjugate, and TNF-α and HRP conjugate biotinylated specific antibody before being incubated. At a wavelength of 450 nm, the optical density of TNF-α coupled with the biotinylated detection antibody was quantified spectrophotometrically.

2.6.4 Estimation of vascular endothelial growth factor (VEGF)

VEGF kit was purchased from Millipore ELISA Kit, USA, Cat No. QIA52. Rat anti-VEGF antibodies were coated on ELISA microplates. Following adding samples or standards, each well received an HRP conjugate and biotinylated antibody that is specific for rat VEGF before being incubated. At a wavelength of 450 nm, the optical density of VEGF coupled with the biotinylated detection antibody was quantified spectrophotometrically.

2.7 Assays of antioxidants/prooxidants in the cerebrum

2.7.1 Estimation of reduced glutathione (GSH) content

The analysis was conducted using a commercial kit (Bio-diagnostic, Giza, Egypt; CAT # GR2511). In theory, the 5-thio-2-nitrobenzoic acid (TNB) yellow color results from the reduction of 5,5'-dithiobis (2-nitrobenzoic acid; DNTB) with GSH in the sample. The sample's GSH content was identified by estimating the decreased chromogen's absorbance at 405 nm.

2.7.2 Estimation of superoxide dismutase (SOD) activity

The test was conducted utilizing a commercial kit (Bio-diagnostic, Giza, Egypt; CAT # SD2521). In theory, nitro-blue tetrazolium was added to NADH, followed by the addition of phenazine methosulphate (PMS) prior to measurement. By estimating the increase in absorbance at 560 nm, the percentage of inhibition brought on by the presence of SOD in the sample could be measured.

2.7.3 Estimation of malondialdehyde (MDA) content

The analysis was conducted using a commercial kit (Bio-diagnostic, Giza, Egypt; CAT # MD2529). The malondialdehyde (MDA) in the sample interacted with thiobarbituric acid in an acidic medium to form a pink color of thiobarbituric acid reactive product that was detected at 534 nm.

2.8 RNA Isolation and qRT-PCR Examination

Cerebrum retained parts (6 specimens/6 rats/parameter/group) were sent to the Research Park (CURP) for further processing. Utilizing a Thermo Scientific RNA purification kit (K0732, Thermo Fisher Scientific, MA, USA), total RNA was isolated using the Trizol agent. Then, using MuLV reverse transcriptase and oligo-dT primers in accordance with the RevertAid First Strand cDNA Synthesis Thermo Scientific kit instructions (K1622, Thermo Fisher Scientific, Waltham, MA, USA), RNA was reverse transcribed into cDNA. The primer sets selected (Table 1) for the SYBR Green master mix analysis of the generated cDNA in a total volume of 10 μl. The PCR thermal cycles included firstly, denaturation for 10 min at 95 °C, followed by 40 cycles of denaturation for 15 s at 95 °C, annealing for 1 min at 60 °C, and extension at 60 °C for 60 s. Non-template and water controls were used to differentiate non-specific amplifications. Data from amplification were examined using 2−ΔΔCt technique [51]. Notably, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-actin were used as reference genes to standardize all values.

Table 1 Primers used for real-time PCR analysis
Full size table

2.9 Statistical analysis

SPSS version 26 for Windows (SPSS Inc., Chicago, IL, USA) was utilized to achieve the statistical analysis. The Least Significant Difference (LSD) test is then used to compare multiple groups to one another. Results were provided as mean and standard error (SE), and one-way ANOVA was used for all statistical comparisons. P values less than 0.05 were regarded as significant, P values less than 0.01 as very significant, and P values greater than 0.05 as nonsignificant.

3 Results

3.1 Cerebral histopathology

Most of the cerebral sections treated with caffeine (group II) showed loss of cerebral cortical layers organization (Fig. 1B) compared to the control group (Fig. 1A). A marked extensive congestion, hemorrhage of cerebral blood vessels, neuronophagia, gliosis, and perivascular/perineuronal edema were observed. The molecular layer presented a considerable number of shrunken and vacuolated neurons. Many neurons showed pyknotic or karyolytic nuclei (Fig. 1B). On the other hand, N-CUR-treated rats (group III) revealed the previously mentioned cerebral neuropathology, but with less severity and extension. In other words, there was a mild to moderate ameliorative impact of N-CUR on caffeine-induced neuropathology in rats (Fig. 1C).

Fig. 1
figure 1

Representative photomicrographs of rat cerebral cortices sections stained with Hematoxylin–Eosin stain (magnification 100 X): (A) control rats (group I) revealed the regular arrangement of six layers of the cerebral cortex, named from the outer to the inner into; outer molecular (plexiform) layer (black arrow) covered with pia matter (bent arrow), external granular layer (blue arrow), pyramidal cell (PYM), internal granular layer (violet arrow), internal pyramidal layer (thin black arrow), and lastly the polymorphic cell layer (orange arrow). (B) The caffeine group (group II) showed congestion (thin black arrow) and hemorrhages (thick black arrow) of cerebral blood vessels, neuronphagia, gliosis, and perivascular/perineuronal edema (thick black arrow). The molecular layer presented a considerable number of shrunken and vacuolations (V). Many neurons showed pyknotic (thick black arrow) or karyolytic nuclei. (C) Rats treated with N-CUR presented a mild to moderate ameliorative effect of caffeine-induced neuropathology (necrobiotic and vascular changes)

Full size image

3.2 Cytokines and inflammatory mediators

Administration of caffeine caused a significant (p < 0.05; LSD) increase in COX-2 level (Fig. 2) and a highly noteworthy (p < 0.01; LSD) increase in IL-6 (Fig. 3), TNF-α (Fig. 4), and VEGF (Fig. 5); compared to the control one. The recorded percentage change was 16.3%, 19.4%, 27.3%, and 9.4%, respectively. Administration of N-CUR results in a nonsignificant (p > 0.05; LSD) improvement in COX-2 levels and a highly significant (p < 0.01; LSD) improvement in TNF-α and IL-6 levels. The recorded percentage changes were − 7.4%, − 21.5%, and − 12.73%, respectively. On the contrary, N-CUR caused a highly significant (p < 0.01; LSD) elevation in VEGF levels; the recorded percentage change was 6.7% compared to the caffeine group.

Fig. 2
figure 2

COX-2 in control, caffeine, and caffeine treated with N-CUR. ( +) significantly changed in contrast to the control group, and (#) nonsignificantly changed in contrast to the caffeine group

Full size image
Fig. 3
figure 3

IL-6 in control, caffeine, and caffeine treated with N-CUR. ( +) significantly changed in contrast to the control group, and (*) significantly changed in contrast to the caffeine group

Full size image
Fig. 4
figure 4

TNF-α in control, caffeine, and caffeine treated with N-CUR. ( +) significantly changed in contrast to the control group, and (*) significantly changed in contrast to the caffeine group

Full size image
Fig. 5
figure 5

VEGF in control, caffeine, and caffeine treated with N-CUR. ( +) significantly changed in contrast to the control group, and (*) significantly changed in contrast to the caffeine group

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3.3 Cerebral antioxidant/oxidative markers

Caffeine administration resulted in significant changes in the antioxidant/oxidative markers (GSH, SOD, and MDA) in the cerebrum in contrast to the control one, as shown in Fig. 6A–C. The percentage of changes was − 11.5%, − 28.0%, and 60.68%, respectively. Administration of N-CUR induced a profound (p < 0.05; − 14.2%) reduction in the GSH level, a highly significant (p < 0.01; 45.2%) increase in the SOD level, and mitigated a non-noteworthy (p > 0.05; − 1.3%) decrease in the MDA level as compared to the caffeine group.

Fig. 6
figure 6

A: Cerebral GSH in control, caffeine, and caffeine treated with N-CUR; B: Cerebral SOD in control, caffeine, and caffeine treated with N-CUR; and C: Cerebral MDA in control, caffeine, and caffeine treated with N-CUR. ( +) significantly changed in contrast to the control group; (*) significantly changed in contrast to the caffeine group; and (#) nonsignificantly changed as compared to the caffeine group

Full size image

3.4 Cerebral Nrf2 and NF-κB gene expression

The caffeine-treated group exhibited a highly substantial (p < 0.01; LSD) downregulation of gene expression of Nrf2 (Fig. 7) and upregulation of gene expression of NF-κB (Fig. 8) in contrast to the control group. Furthermore, administration of N-CUR induced a nonsignificant (p > 0.05; LSD) upregulation in Nrf2 gene expression and a highly significant (p < 0.01; LSD) downregulation of NF-κB expression as compared to the caffeine group.

Fig. 7
figure 7

Cerebral Nrf2 expression in control, caffeine, and caffeine treated with N-CUR. ( +) significantly changed in contrast to the control group, and (#) nonsignificantly changed in contrast to the caffeine group

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Fig. 8
figure 8

Cerebral NF-κB expression in control, caffeine, and caffeine treated with N-CUR. ( +) significantly changed in contrast to the control group, and (*) significantly changed in contrast to the caffeine group

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4 Discussion

Due to the fact that excessive doses of caffeine may have harmful effects on the brain [13, 69, 85], and N-CUR has a positive impact on improving a wide range of diseases, including neurological disorders [31], the current study aims to examine the protective effect of N-CUR (300 mg kg−1) on caffeine (150 mg kg−1)-induced alterations in the cerebrum of male albino rats, focusing on biochemical, histopathological, and qRT-PCR assays. In general, caffeine can affect the cerebrum due to its stimulatory effect on the hypothalamic-pituitary axis and CNS [54] and its insulinotropic effect, which results in energy loss and an increase in intracellular calcium concentration [20].

The primary observation of the current study is that there was a loss in the organization of the cerebral cortical layers, significant cerebral blood vessel congestion and hemorrhages, neuronophagia, gliosis, perivascular/pericellular edema, and numerous vacuolations in the molecular layer. Consuming high concentrations of caffeine may induce cellular apoptosis [53]. These pathological lesions are consistent with the unbalanced egress of reactive oxygen species (ROS) in the caffeinated group. Caffeine may enhance LPO, which may encourage the formation of free radicals and cause a rise in oxidative stress [77]. The production of ROS is linked to aging and several chronic diseases [39]. However, the half-life of ROS is so short that its concentration cannot be measured directly. Thus, we have measured changes in MDA, GSH, and SOD levels, which are signs of oxidative stress [1]. The current study reported that exposure of male rats daily to 150 mg of caffeine for one month resulted in a profound elevation in cerebral MDA. Leelarungrayub et al. reported that consuming caffeinated coffee resulted in increased MDA levels as compared to consuming decaffeinated coffee [48]. Also, Metro et al. displayed that consuming foods with high concentrations of caffeine caused an increase in intramuscular fat oxidation [59]. In parallel, a reduction in cerebral GSH content was recorded in the caffeinated group. This reduction in GSH may be induced by the depletion of nicotinamide adenine dinucleotide phosphate (NADPH) or by raised GSH consumption during the non-enzymatic elimination of oxygen radicals [28]. Depletion of intracellular GSH significantly increases the generation of ROS in the mitochondria and results in depolarization of the mitochondrial membrane [52]. Alternatively, a reduction in cerebral SOD activity was recorded in the caffeinated group. Cruz et al. concluded that caffeine caused an oxidative state in rats and decreased GSH content and SOD activity, respectively [17]. This disturbance, which might be attributed to consuming caffeine during an acute inflammatory response, might cause tissue damage because it suppresses adenosine 2a receptor (A2aR)-mediated adenosine signaling, which is an essential tissue-protective mechanism [64]. Generally, caffeine binds to adenosine receptors and blocks the neurotransmitter's function [93].

These pathological changes and oxidative stress states were mild to moderately ameliorated by N-CUR (300 mg kg−1). This result was supported by a nonsignificant decrease in the level of MDA and an elevation in SOD activity, but failed to increase the GSH content. This partial ameliorative effect of N-CUR might be caused by CUR's antioxidant and anti-inflammatory impacts on a variety of molecular targets, which have therapeutic impacts on various chronic inflammatory diseases [23] by inhibiting ROS generation [9]. Biological investigations revealed that CUR might be considered a potent antioxidant that stops cellular proliferation by liberating active free thiol groups at target sites [4]. CUR's antioxidant properties may result from the following interactions: free radicals scavenging by oxygen quenching, inhibition of cytochrome P450, or chelating oxidative properties of metal ions [70]. According to a study, CUR inhibits the oxidation of Fe2+ in the Fenton reaction, which prevents the production of hydroxyl radical and superoxide anion [21]. Thus, N-CUR may revoke the oxidative imbalance and mitigate the cerebral histopathology induced by caffeine.

In the present study, a significantly elevated production of TNF-α and IL-6 (pro-inflammatory mediators) was observed in the caffeinated group. Overproduction of TNF-α and IL-6 as an inflammatory response might cause several pathological consequences [81]. However, these cytokines have multifunctional actions for immunity, angiogenesis, apoptosis, and inflammation [29, 63, 65, 73]. In disagreement with the present data, the IL-6 and TNF-α levels were decreased after exposure of KK-A(y) mice to caffeine [92]. This diminution could be ascribed to the inhibition action of caffeine on the inflammatory pathways or the phosphorylated STAT1 mechanism [36]. On the contrary, administration of N-CUR herein exhibited anti-inflammatory and chemo-preventive effects where the levels of TNF-α and IL-6 were substantially ameliorated. Several publications have presented the therapeutic effects of CUR on these cytokines. Ghandadi and Sahebkar reported that CUR was used as a potential treatment for pathological values ​​involving IL-6 [27]. Aggarwal et al. stated that CUR could block the action and production of TNF-α [3]. Shehzad et al. revealed that CUR reduced neuroinflammation by lowering IL-1β and TNF-α [80]. Thus, the administration of N-CUR attenuated the neuroinflammatory state induced by caffeine.

The present research revealed that exposure of rats to 150 mg of caffeine resulted in significantly increased COX-2 and VEGF levels. In agreement, Han et al. reported that caffeine promoted the initiation of apoptosis through COX-2 pathways [30]. Notably, the expression of COX-2 is noticeably upregulated in astrocytes and microglia during the neuroinflammatory response [24]. A neuroinflammatory response is caused by activated neuronal COX-2 and microglial cells, which produce and express IL-6 and TNF-α [84]. The stimulation of COX-2 has been related to an increment in VEGF production and angiogenesis [86]. The alteration in growth markers might be attributed to the fact that caffeine can diminish the activity of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and induce the cAMP-dependent protein kinase (PKA) [16, 62]. Administration of N-CUR (300 mg kg−1) resulted in a nonsignificant amelioration of COX-2 and VEGF levels. This alteration could be elucidated by the considerable oxidative stress and inflammation related to caffeine administration. However, other studies found that CUR inhibits the activity of COX-2 [60] and reduces VEGF levels [74].

The current study also followed the mRNA expression of two vital transcription factors, which are responsible for the transient response to cellular stresses. Also, nuclear factor erythroid 2-related factor 2 (Nrf2) can be targeted to provide cell protection [18] via the regulation of antioxidant genes and suppression of oxidative stress [76]. Nuclear factor κB (NF-κB) contributes to harmful cell impact [11]. These factors may regulate cellular reactions to inflammation and oxidative stress. Inhibition of Nrf2 expression and stimulation of NF-κB expression were observed in the caffeinated group. This result largely agrees with the data of Kang et al. [42]. Similarly, Ito et al. stated that DNA synthesis and the cell cycle could both be inhibited by caffeine [37]. Cell death initiation by caffeine was facilitated by NF-κB [42], Cox2 [89], mitogen-activated protein kinase, and extracellular signal-regulated kinases [72] pathways. These changes might reflect the degree of degeneration in the cerebral cortex, inflammation, and oxidative stress and might be a sign of neural disorders. Although N-CUR (300 mg kg−1) administration had a nonsignificant effect on Nrf2 expression, NF-κB was significantly downregulated. In cell lines, CUR may exert effective results via the regulation of Nrf2 [26]. CUR can activate the Nrf2 signaling pathway in response to stress and decrease electrophiles and ROS levels [26]. Activation of NF-κB produces several mediators that jointly cause neuroinflammation [53]. In the current data, N-CUR inhibited pro-inflammatory cytokines and NF-κB in the cerebrum of the caffeinated group. The inflammatory reaction noticed in caffeine-treated rats might be due to elevated ROS production [46]. ROS production can lead to the stimulation of NF-κB followed by the release of many inflammatory mediators [43]. In agreement, Wang et al. stated that NF-κB inhibition might be a key mechanism underlying CUR's anti-inflammatory effects [90]. CUR exhibits the capability to inhibit NF-κB in the treatment of several illnesses, involving ulcerative colitis [90], acute kidney injury [99], and lipopolysaccharide (LPS)-induced neuroinflammation [94]. Collectively, the bioavailability and neuroprotective efficiency of CUR could be attributed to piperine alkaloids [8]. In general, Li et al. (2023) stated that CUR could enhance neuroprotective mechanisms by controlling neurogenesis.

5 Conclusion

These data suggest new findings on the moderate ameliorative effect of N-CUR on cerebral disorders induced by a high dose of caffeine administration. N-CUR diminished cell death, oxidative stress, and inflammation in the cerebrum of caffeine-administered rats as it resulted in a significant improvement in TNF-α and IL-6 levels and a significant elevation in SOD activity; furthermore, it significantly downregulated NF-κB mRNA expression. These data recommend that humans should limit caffeine intake to avoid any adverse problems. Additional investigations into human health should be required.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

A2aR:

Adenosine A2 receptors

AKT:

Protein kinase B

COX-2:

Cyclooxygenase-2

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CUR:

Curcumin

DNTB:

5, 5: -Dithiobis (2-nitrobenzoic acid)

ERK:

Extracellular signal-regulated kinase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GSH:

Reduced glutathione

HRP:

Avidin-horseradish peroxidase

H2O2 :

Hydrogen peroxide

IL-6:

Interleukins -6

LPS:

Lipopolysaccharide

LSD:

Least significant degree

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

NADPH:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor kappa B

Nrf2:

Nuclear factor erythroid 2-related factor 2

NBF:

Neutral buffered formalin

NBT:

Nitro-blue tetrazolium

N-CUR:

Nano-curcumin

PBS:

Phosphate-buffered saline

PD:

Parkinson’s disease

PI3K:

Phosphatidylinositol-3-kinase

PKA:

Protein kinase A

PMS:

Phenazine methosulphate

PYM:

Pyramidal cell

ROS:

Reactive oxygen species

qRT-PCR:

Quantitative reverse transcription polymerase

SE:

Standard error

SOD:

Superoxide dismutase

SPSS:

Statistical package for the social sciences

SVZ:

Subventricular zone

TBA:

Thiobarbituric acid

TNF-α:

Tumor necrosis factor

VEGF:

Vascular endothelial growth factor

V:

Vacuoles

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Acknowledgements

The authors thank the Department of Biochemistry and Zoology members, Faculty of Science, Beni-Suef University, for providing the lab facilities for the present research work.

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  1. Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt

    Moustafa M. Morsy & Mohammed Abdel-Gabbar

  2. Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt

    R. G. Ahmed

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  1. Moustafa M. Morsy
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Moustafa M. Morsy1 contributed to formal analysis, methodology, resources, software, writing – original draft preparation, and Ahmed R.G.2 and Mohammed Abdel-Gabbar1 contributed to conceptualization, formal analysis, methodology, project administration, resources, software, supervision, visualization, writing – review & editing.

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Correspondence to R. G. Ahmed.

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Morsy, M.M., Ahmed, R.G. & Abdel-Gabbar, M. Nano-Curcumin improves caffeine-induced cerebral alterations in male Wistar rats by modifying oxidative stress, inflammation, and COX-2/NF-κB/Nrf2 signaling. Beni-Suef Univ J Basic Appl Sci 13, 93 (2024). https://doi.org/10.1186/s43088-024-00526-5

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