Introduction

One of the most commonly used medications for treating schizophrenia, alcohol withdrawal syndromes, Alzheimer’s disease (AD), acute manic and mixed episodes in bipolar I disorder, trigeminal neuralgia, epileptic seizures, and neuropathic pain is carbamazepine (CBZ), which is marketed as Tegretol (Eshiet et al. 2020; Sukkarieh et al. 2023). Administration of CBZ for extended periods, however, has been linked to several adverse side effects, including kidney diseases, testicular dysfunction, liver damage, and metabolic disorders (Iida et al. 2015; Osuntokun et al. 2017). Despite this medical knowledge, few studies have focused on CBZ-induced renal damage. One of the studies reported that renal failure occurred in a 68-year-old Alzheimer’s patient who had started using CBZ for her epilepsy (Koda et al. 2012). CBZ-induced damages may involve multiple organs, resulting into effects ranging from interstitial nephritis to fatal adrenalitis. Previous studies demonstrated that patients with AD who took CBZ developed nephropathy, granulomatous interstitial nephritis, itchy skins lesions, acute necrosis and exanthematic pustulosis which are collectively considered to be anticonvulsant hypersensitivity syndrome (Sangeetha et al. 2014; Hamed et al. 2018). To date, the primary mechanism of CBZ-induced kidney toxicity remains incompletely elucidated. It has been recently suggested that CBZ-induced renal damage may be due to its ability to trigger oxidative stress as well as apoptosis (Guzel et al. 2023). Such CBZ-induced destruction of cellular antioxidant systems (along with its metabolite, carbamazepine-10, 11-epoxide) promotes oxidative stress and damage in biological systems (Iida et al. 2015). Thus, there is a dire need to identify potential natural compounds that can neutralize the side effects of CBZ when administered to patients.

Matricin (1) is the major phytochemical in the leaves and flower heads of chamomile (Matricaria chamomilla L., Asteraceae), a species that has been utilized for centuries to treat diseases characterized by inflammation (Srivastava et al. 2010; Zhang et al. 2014; Mailander et al. 2022; Nakurte et al. 2023). The sesquiterpene lactone, matricin, has also been identified in Artemisia absinthium L. As a precursor to chamazulene, the anti-inflammatory activity of matricin has been established to occur through its conversion to chamazulene carboxylic acid (Ramadan et al. 2006; Goud et al. 2015). This study was undertaken to establish the renoprotective effect of matricin against CBZ-induced acute tubulointerstitial nephritis in rats with AD. The underlying mechanisms were also explored since no such study giving a mechanistic insight into CBZ-induced toxicity has been undertaken before.

Materials and Methods

Chemicals and Reagents

For the present study, matricin (batch no. BCBD4718V) and carbamazepine (batch no. C4024) were purchased from Sigma Aldrich (St. Louis, Missouri, United States). All the other chemicals and reagents, unless otherwise stated, were of analytical grade and were used as obtained without further purification.

Acute Toxicity Assay

The acute oral toxicity of matricin was assessed in Sprague Dawley rats (150–200 g) following the guidelines of the Organization for Economic Cooperation and Development guideline 423 (OECD 2002). All the rats were fasted overnight before each trial, and were randomly allocated into four groups (n = 5). The 1st group was a negative control, 2nd, and 3rd, 4th were the tested groups, which were only given matricin orally at doses of 300, 1000 and 2000 mg/kg body weight. The initial body weight of each rat was measured. For the first 4 h after the treatment period, the animals were monitored for any harmful effects and changes in behavior, breathing, skin effects, water consumption, food intake, and temperature were detected.

Subacute Toxicity Assay

The subacute toxicity assay was performed with three doses (50, 100, and 150 mg/kg) of matricin for 28 days. The health markers, including weight fluctuations, food, and fluid intake were observed. Biochemical assays such as complete blood chemistry and biomarkers of liver and kidney functions were detected.

Experimental Approach

Thirty-five male Sprague Dawley rats weighing ~ 100 g (4 weeks old) was housed in cages at room temperature under a 12-h light/dark cycle. The rats were allocated into seven groups (5 rats/group) randomly (Fig. S1).

Dose Administration

The route of administration of CBZ and matricin doses was oral while scopolamine doses were intraperitoneally injected. The CBZ and matricin doses were prepared in deionized water, and administrated daily for 28 days. The standard CBZ anticonvulsant dosage of 25 mg/kg/day for humans was used while the 50 mg/kg dose of matricin was chosen from the subacute toxicity assay. Onset of AD was triggered after the final drug administration, which involved single i.p. injection of scopolamine at a dose of 16 mg/kg (El-Marasy et al. 2012, 2018). Scopolamine administration is considered to be a psychopharmacological model of AD (Bajo et al. 2015).

Allocation of Groups

The following groups of rats were allocated;

Control group: rats were only drinking water and feeding.

AD control group: scopolamine (16 mg/kg) was i.p. injected in rats as a single dose on the 28th day to induce AD.

ATN control group: CBZ was given orally to rats at 25 mg/kg once a day to induce acute tubulointerstitial nephritis (ATN).

Scopolamine + CBZ group: CBZ was given orally to rats at 25 mg/kg once a day and a single i.p. injection of scopolamine (16 mg/kg) on the 28th day.

Matricin group: rats received matricin (50 mg/kg) orally once a day.

Matricin + scopolamine group: rats received matricin (50 mg/kg) orally once a day and a single i.p. injection of scopolamine (16 mg/kg) on the 28th day.

Matricin + CBZ + scopolamine group: rats received matricin (50 mg/kg) and CBZ (25 mg/kg) via oral gavage once a day. Single i.p. injection of scopolamine (16 mg/kg) was done on the 28th day.

Biochemical Analysis

At the time of sacrifice, blood was collected and stored in tubes containing a blood clotting activator. The serum underwent centrifugation at 2,000 x g for 10 min and then kept at 4 oC for 10 min. This was done to conduct biochemical analysis which evaluated the biomarkers associated with kidney function namely: uric acid, creatinine, and blood urea nitrogen (abbreviated as UA, CRT, and BUN, respectively). The biochemical analysis was conducted using the Chemistry Analyzer Tecno 786.

Tissue Collection

Rats were fasted overnight and anesthetized with ketamine hydrochloride (30 mg/kg body weight) for sacrifice at the end of the experiment. The organs of each rat in the control and treated groups were excised, and rinsed with ice-cold phosphate buffered saline at the time of sacrifice. The organs were labeled according to their cohort. At -80 °C, some parts of the targeted organs (liver and kidneys) were preserved. The preserved tissue sample of 100 g was weighed and homogenized in Tris-HCl (0.1 M) and centrifuged at 7000×g for 2 min at 4 oC. The supernatant was either used immediately or stored at -20 °C until required for analysis.

Evaluation of Malondialdehyde

A mixture of sodium dodecyl sulfate (0.2 ml), 0.8% thiobarbituric acid, 10% tissue homogenate, and 20% acetic acid was prepared. The mixture (4 ml) was boiled for 1 h at 95 0C. Thereafter, 5 ml of pyridine: n-butanol (1:15) was mixed with 1 ml of distilled water, centrifuged and its absorbance was observed at 532 nm ( Iqbal et al. 2023a).

Determination of Catalase

The reaction mixture consisted of 0.4 ml of 5.9 mM H2O2, 2.5 ml of 50 mM phosphate buffer (pH 5), and 0.1 ml of enzyme extract. At 240 nm, a change in the absorbance of the mixture was recorded.

Determination of Superoxide Dismutase

The reaction mixture comprised of sodium pyrophosphate buffer (0.052 mM; pH 7; 1.2 ml) and phenazine methosulphate (186 mM; 0.1 ml). After centrifuging the tissue homogenate (1500 × g for 10 min and then 10,000 × g for 15 min), 0.3 ml of the supernatant was added to the solution. The enzyme reaction was started by adding NADH (780 mM; 0.2 ml). The reaction was stopped by adding glacial acetic acid (1 ml). Finally, the amount of chromogen was determined by observing the colour intensity change at 560 nm. SOD activity levels were expressed as units/mg of protein.

Synthesis of cDNA

A High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, USA) was used to synthesise cDNA. A reaction combination with a total volume of 20 µl was used for reverse transcription (RT) containing reverse transcriptase (1 µl), 10 µl of RNA (800 ng), 2 µl of RT random primers (100 mM), 2 µl of RT buffer (10×) and 0.8 µl of deoxynucleoside triphosphate (25×). The reactions were incubated for 10 min at 25 °C, 120 min at 37 °C, 5 min at 85 °C, and 10 min at 4 °C (Bahari et al. 2017).

Protocol of qRT-PCR

In the experiment, 0.5 µl of primers (Table S1) were mixed with cDNA (1 µl), SYBR Green qPCR Mix 2 × (10 µl), nuclease-free water (8 µl), and the genes RAS, RAF, AKT, JAK2, MEK, ERK1, ERK2, STAT3, and β-actin (used as a house-keeping gene). The research was conducted using the Rotor-Gene® QqPCR (QIAGEN®) instrument. The procedure was completed with a final extension phase that lasted for 10 min at 72 °C. The secondary incubation process was then carried out at 95 °C for 1 min. The melting procedure was carried out by gradually raising the temperature from 54 to 95 °C for around 3–5 min. A single peak was obtained from a melting curve study that was carried out after each PCR product was amplified (Mohammadi et al. 2014; Rassouli et al. 2023).

ELISA

The cytokines (TNF-α, IL-6, and IL-β) were determined by ELISA kits (R&D Systems, Inc.) using serum according to the standard protocol used previously in our laboratory (Iqbal et al. 2023b), with slight modifications. Measured 50 ml of assay diluent and 10 ml of plasma were poured into a 96-well ELISA plate and then incubated at room temperature for 2 h. After that, the plates were washed with deionized water before adding 100 ml of peroxidase-conjugated immunoglobulin G (IgG) anti-TNF-α, anti-IL-1β, and anti-IL-6 solution in each well and incubating for 2 h. Plates were rewashed with deionized water, then to them was added the substrate solution and incubated for 25 min at room temperature. To stop the reaction, 50 ml of the stop solution was applied to each well. At 450 nm, the absorbances of TNF-α, IL-1β, and IL-6 were measured by a plate reader (Apollo 11 LB 913 ELISA Reader). All the samples were run in triplicate under the same conditions.

Histological Analysis

Kidney tissues were fixed in 10% formalin, and then embedded in paraffin wax. Richert microtome was used to cut slices of 5 μm thick, which were subsequently placed on the slides. The tissues on the slides were stained with hematoxylin and eosin, and deparaffinized overnight at 60 °C. Ultimately, a light microscope (Nikon, Japan) equipped with an automated microphotography system was used to examine the slides. The images were analysed using ImageJ software.

Statistical Analysis

Analysis of variance (ANOVA) in the general linear model was used to determine the statistical difference between groups, at a 5% level of significance, and Tukey’s posthoc test was performed to compare the varying groups by using GraphPad Prism version 9.0 (GraphPad Software, La Jolla, California).

Results and Discussion

Acute Oral Toxicity

There were no toxicity signs observed in rats administered the highest dose of matricin. Thus, the LD50 of matricin was established to be greater than 2000 mg/kg, implying that it could be considered to be safe in rats with AD.

Subacute Toxicity

The food and fluid intake as well as weight in all the matricin-treated groups were optimized. All the parameters of biochemical analysis of liver and kidney function tests, and hematological analysis were in the normal range in the 50, 100 and 150 mg/kg treatment groups. Hence, we chose the lowest dose (50 mg/kg) of matricin for the current study.

Kidney Function

Serum analysis recorded a significant increase (p < 0.01) in the levels of biomarkers of kidney function, including blood urea (BUN), creatinine (CRT), and uric acid (UA) in only CBZ treated rats with AD acute tubulointerstitial nephritis. On the other hand, administration of matricin + CBZ to rats with AD and ATN reinstated the levels of CRT, BUN, and UA (p < 0.001) (Fig. 1).

Fig. 1
figure 1

Matricin + carbamazepine treatments alleviated the level of blood urea nitrogen, creatinine, and uric acid in Alzheimer’s disease rats than only carbamazepine treated rats of the Alzheimer’s disease model. Values expressed as means ± standard errors. CBZ + SCO group: CBZ (25 mg/kg) + SCO (16 mg/kg); MT group: MT (50 mg/kg); MT + SCO group: MT (50 mg/kg) + SCO (16 mg/kg); MT + CBZ + SCO group: MT (50 mg/kg) + CBZ (25 mg/kg) + SCO (16 mg/kg). The F-values were: blood urea nitrogen (F-value = 20.47), creatinine (F-value = 38.12), and uric acid (F-value = 23.79). ***p < 0.001, **p < 0.01, vs. CZ + SCO group; ###p < 0.001 vs. control group as per Tukey’s posthoc test. CBZ: carbamazepine; SCO: scopolamine; MT: matricin

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Antioxidant Level Improvements

It was observed that matricin + CBZ treatments alleviated MDA concentration prominently (p < 0.001) and elevated SOD and CAT levels significantly (p < 0.001) in rats with AD and acute tubulointerstitial nephritis than in rats with AD and ATN which received CBZ only as shown in Fig. 2.

Fig. 2
figure 2

Levels of malondialdehyde, catalase, and superoxide dismutase were optimized after matricin + carbamazepine treatments than only carbamazepine-treated rats with Alzheimer’s disease Values represented as means ± standard errors. MT + SCO group: MT (50 mg/kg) + SCO (16 mg/kg); MT + CBZ + SCO group: MT (50 mg/kg) + CBZ (25 mg/kg) + SCO (16 mg/kg), MT group: MT (50 mg/kg); CBZ + SCO group: CBZ (25 mg/kg) + SCO (16 mg/kg). The F-values were: Superoxide dismutase (F-value = 16.49), malondialdehyde (F-value = 13.84), and Catalase (F-value = 17.02). ***p < 0.001, **p < 0.01, vs. CZ + SCO group; ###p < 0.001 vs. control group as per Tukey’s posthoc test. CBZ: carbamazepine; SCO: scopolamine; MT: matricin

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Anti-inflammatory Effects

The serum levels of TNF-α, IL-1β, and IL-6 were significantly (p < 0.001) aggravated in rats with AD and ATN that received only CBZ (25 mg/kg) when compared with the control. Co-administration of matricin + CBZ in rats with AD and ANT alleviated inflammatory cytokines production (Fig. 3).

Fig. 3
figure 3

ELISA results showed matricin + carbamazepine treatments alleviated inflammatory cytokines (IL-6, IL1β, and THNF-α) than only carbamazepine-treated rats with Alzheimer’s disease. Values are means ± standard errors. MT + CBZ + SCO group: MT (50 mg/kg) + CBZ (25 mg/kg) + SCO (16 mg/kg); CBZ + SCO group: CBZ (25 mg/kg) + SCO (16 mg/kg); MT group: MT (50 mg/kg); MT + SCO group: MT (50 mg/kg) + SCO (16 mg/kg). The F-values were: IL-16 (F-value = 11.38), IL-1β (F-value = 21.39), and TNF-α (F-value = 9.093). ***p < 0.001, **p < 0.01, vs. CZ + SCO group; ###p < 0.001 vs. control group as per Tukey’s posthoc test. CBZ: carbamazepine; SCO: scopolamine; MT: matricin

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RAS/RAF/ERK/MEK/JAK2/STAT3 Signaling

The findings of qRT-PCR revealed that there was significant (p < 0.001) upregulation of mRNA expressions of RAS, RAF, ERK1/2, MEK, JAK2, and STAT3 in rats with AD and ATN that received only CBZ than in the control group. Evidently, matricin + CBZ co-administration significantly inhibited the expressions of ERK1/2, MEK, RAF, RAF, STAT3, and JAK2 (p < 0.001) in rats with AD and ATN (Fig. 4).

Fig. 4
figure 4

The RAS/RAFMEK/ERK/STAT3 signaling pathway activated in rats with Alzheimer’s disease (AD) with tubulointerstitial nephritis. Detection of relative mRNA expression of ERK1/2 M MEK, JAK2, STAT3, and RAS/RAF in control, AD, and AD rats with tubulointerstitial nephritis carried out by qRT-PCR analysis. The mRNA levels of (a) ERK1, (b) RAS, (c) RAF, (d) STAT3, (e) JAK2 (f) ERK2 and (g) MEK was upregulated in only carbamazepine-treated AD rats in contrast the respective mRNA RNA expressions were downregulated in matricin + carbamazepine-treated AD rats. Values are means ± standard errors of replicates. CBZ + SCO group: CBZ (25 mg/kg) + SCO (16 mg/kg); MT + CBZ + SCO group: MT (50 mg/kg) + CBZ (25 mg/kg) + SCO (16 mg/kg); MT group: MT (50 mg/kg); MT + SCO group: MT (50 mg/kg) + SCO (16 mg/kg). The F-values were: RAS (F-value = 11.71), RAF (F-value = 10.88), MEK (F-value = 5.10), ERK1 (F-value = 19.31), ERK2 (F-value = 3.014), JAK2 (F-value = 4.262) and STAT3 (F-value = 3.412). ***p < 0.001, **p < 0.01, vs. CZ + SCO group; ##p < 0.001 vs. control group as per Tukey’s posthoc test. CBZ: carbamazepine; SCO: scopolamine; MT: matricin

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Kidney Histoarchitecture

Histopathological analysis of the kidney sections revealed that there were significant inflammatory changes (tubular necrosis, systemic dilation, glomerulus nephritis, and interstitial edema) in CBZ-treated rats of the AD model (Fig. 5d) than in the control (Fig. 5a). The histoarchitecture of rats only treated with matricin (Fig. 5e) and co-treated with matricin and CBZ (Fig. 5f) showed normal arrangement of tubular structures around the glomerulus. Kidney histoarchitecture was restored with only mild glomerulus sclerosis following co-administration of matricin and CBZ to rats of the AD model (Fig. 5g).

Fig. 5
figure 5

Histology following hematoxylin and eosin stain: (a) and (b) micrograph showing typical histoarchitectural arrangements in the kidney section of control; (c) histoarchitecture of the ANT-control (only treated with CBZ at 25 mg/kg) with marked glomerulus fibrinoid necrosis (red arrow), vascular dilation (black arrow), cloudy swelling, and tubular nephritis (blue arrow). Most of these kidney injuries were due to severe necrosis; (d) 40× hematoxylin and eosin marks tubular nephritis (blue arrow), vascular dilation (black arrow), glomerulus fibrinoid necrosis (red arrow), cloudy swelling (e) 40× hematoxylin and eosin) expresses normal histoarchitecture in rats only treated with MT (f) micrograph shows the typical arrangement of tubular structure around the glomerulus in only MT-treated rats with Alzheimer’s disease. (g) 400× hematoxylin and eosin) shows the typical arrangement of the tubular structure and observed mild glomerulus sclerosis (black arrow) in MT + CBZ-treated rats with Alzheimer’s disease. All micrographs are at scale bar = 100 μm. CBZ: carbamazepine; MT: matricin

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Patients with AD are six to ten times more likely to experience epilepsy during their illness than healthy people of the same age. It has been shown that 9.6% of AD patients in a retrospective autopsy investigation experienced an unprovoked seizure and 6% epilepsy following the development of AD (Tombini et al. 2021). Carbamazepine appears to have modest efficacy in managing epilepsy and other behavioral symptoms associated with various psychiatric disorders in AD patients (Dyong et al. 2023). Because of the use of CBZ as the first-line medication to treat epilepsy and psychiatric disorders in patients with AD, it is urgent to focus on the mitigation of its side effects which include kidney damage.

In this study, an in vivo AD model was established in Sprague Dawley rats to find out the renoprotective effect of matricin when co-administered with CBZ. An earlier study considered the same experimental approach to find out the combined effect of vitamin C + CBZ in preventing CBZ-induced reproductive damage in rats when compared with CBZ-only treated rats (Akorede 2020). In the context of AD, the therapeutic activity of CBZ for treating epilepsy is achieved through stabilisation of the inactivated voltage-gated sodium channel and activation of GABA receptors through GABA agonist potency, and the release of serotonin (Kawata et al. 2001). However, the effects of matricin on GABA receptors and voltage-gated sodium channel has not yet been established.

The byproduct of lipoperoxidation (MDA) disrupts membrane fluidity and structural integrity, and inactivates enzymes that are embedded in the membrane (Shittu et al. 2012). There is a possibility that reactive oxygen species (ROS) generation in CBZ-exposed mice is responsible for the elevated levels of MDA (Guzel et al. 2023). MDA levels in the kidney homogenate in this study were observed to have decreased after co-treatment of matricin + CBZ in the AD rat model, which is likely attributable to the anti-inflammatory properties of matricin (Ramadan et al. 2006; Goud et al. 2015). The oxidation of hepatocellular membranes by free radicals can be inhibited through pre-treating with chamazulene, a sesquiterpene derivative. The MDA levels increased and anti-oxidative enzymes decreased in the ethanol-induced liver injury model group but decreased MDA, and increased CAT and SOD levels after chamazulene treatment were found (Wang et al. 2020b). This report corroborates the results obtained in this study. Matricin is a sesquiterpene (i.e., a C15-terpenoid comprised of three isoprene units and contains hydrocarbons or oxygenated forms including lactones, alcohols, acids, aldehydes, and ketones). In addition, matricin has free radical scavenging activity and according to its chemical structure 1, it can accept 5 free radicals or hydrogen atoms. This free radical scavenging ability could have resulted in the increased levels of antioxidant enzymes such as catalase, and superoxide dismutase as these enzymes scavenge free radicals in oxidative stress conditions, and their level decreases due to an increased number of free radicals (Goeters et al. 2001). Hence, matricin helped in the present investigation to scavenge free radicals due to CBZ-induced oxidative stress in the AD model rats and indirectly promote the increase in CAT and SOD levels.

figure a

Kidney function tests in the current study indicated that were increased levels of CRT, BUN, and UA in AD model rats which received CBZ only. Co-treatments of matricin + CBZ reinstated kidney function biomarkers in the rats after 28 days. Similar effects were observed in a previous investigation where chamomile flower extract (in which matricin is the major bioactive compound) enhanced kidney function in rats with polycystic ovary syndrome by inhibiting ROS generation and lipid oxidation (Alahmadi et al. 2021).

Inflammatory cytokines have a key role in inducing apoptosis and inflammation. Interleukin 6 plays a supporting role in the pathophysiology of a variety of inflammatory disorders and has recently received much research attention as a result of its major role in inflammatory processes (Li et al. 2021). Previous research suggested that drugs could promote apoptosis by increasing levels of tumor necrosis factor (Fredriksson et al. 2014). The present study recorded a significant (p < 0.01) increase in inflammatory cytokines (IL-16, IL-Iβ, and TNF-α) in rats with AD when they were treated with CBZ only. Conversely, there were reduced levels of inflammatory cytokines after co-treatments of matricin + CBZ at 25 mg/kg for 28 days. In earlier studies, chamazulene (a sesquiterpene derivative, and which matricin is a precursor) reduced pro-inflammatory cytokines in rats with ethanol-induced liver damage owing to an increase in serum levels of antioxidative enzymes (CAT, GPx, and SOD) (Wang et al. 2020b).

ERK1/2/MEK/RAS/RAF are intracellular molecules that regulate different cellular actions including apoptosis, differentiation proliferation, and cytokine secretion (Li and Gobe 2006; Capolongo et al. 2019). Ras-GTP upregulates Raf in a complex fashion to the plasma membrane. After the activation, Raf components upregulate MEK1/2 which later on triggers ERK1/2. The inhibition of ERK-MEK-RAS is the main target for treating disease conditions (Lake et al. 2016). The JAK2/STAT3 pathway plays a significant role in several disease conditions, including kidney disorders, ischemic reperfusion injury, carcinogenesis, and neurodegeneration. This pathway is the transducer of extracellular signals to the nucleus from the cytoplasm (Zhang et al. 2019; Wang et al. 2020a). The present investigation focused on ERK1/2/MEK, JAK2/STAT3, and RAS/RAF as there is no such study which investigated the role of the RAS-ERK-MEK-JAK2/STAT3 signaling pathway of these targeted genes in the treatment of acute tubulointerstitial nephritis. The qRT-PCR data showed that matricin + CBZ co-treatment downregulated mRNA expressions of RAF/RAS, ERK1/2MEK, and JAK2/STAT3 signaling to overcome CBZ-induced acute tubulointerstitial nephritis in rats with AD. Further, qRT-PCR confirmed their relative mRNA expressions (Fig. 3). The pharmacologic effects of matricin on CBZ are exclusively based on gene expression profiling. The present study has proven that the ERK-MEK-RAS-JAK2-STAT3 signaling pathway has a role in CBZ-induced kidney injury, which might be mediated through activation of inflammatory responses. Thus, the matricin + CBZ co-treatments negatively affected the feedback of this pathway. Previous reports showed that cerebral injury in rats was improved on inhibition of the crosstalk of the MEK/ERK/RAS and JAK2/STAT3 signaling by deactivating inflammatory responses (Li et al. 2015; Zang et al. 2019). These reports support our study findings.

Histological analysis was performed to observe the apparent nephroprotective effect of matricin when co-treated with CBZ in rats with AD. The co-treated (matricin + CBZ) rats with Alzheimer’s retained their normal kidney histoarchitecture with mild cloudy swelling and tubular nephritis. A preceding study stated that parthenolide (a sesquiterpene) restored normal kidney histoarchitecture in lipopolysaccharide-induced acute kidney damage in rats. This proceeded through the setback of inflammatory responses (Shou et al. 2023), which support the results observed in the present study.

Conclusion

Our results demonstrated that the nephroprotective effect of matricin is mediated through inhibiting CBZ-induced acute tubulointerstitial nephritis via regulating RAS-MEK-ERK-JAK2-STAT3 signaling, inflammatory responses, and oxidative stress biomarkers. Thus, matricin could be suggested as a co-supplement to Alzheimer’s patients who have been prescribed CBZ to reduce the side effects of CBZ. However, this will necessitate clinical trials to be conducted so as to verify the efficacy of matricin + CBZ in human patients with AD.