Abstract
Microcystis aeruginosa produces an abundant cyanotoxin (microcystins (MCs) in freshwater supplies. MCs have adverse health hazards to animals and humans. Microcystin-leucine-arginine (microcystin-LR or MC-LR) is the most studied among these MCs due to their high toxicity. So, this study was designed to evaluate the possible therapeutic role of the natural algal food supplement, Spirulina platensis (SP), against MC-LR-induced toxic effects in male Wistar rats. Forty rats were randomly divided into five groups. Control and SP groups orally administered distilled water and SP (1000 mg/kg/daily), respectively, for 21 days. MC-LR group was intraperitoneally injected with MC-LR (10 μg/kg/day) for 14 days. MC-LR-SP500 and MC-LR-SP1000 groups were orally treated with SP (500 and 1000 mg/kg, respectively) for 7 days and concomitantly with MC-LR for 14 days. MC-LR induced oxidative hepatorenal damage, cardiotoxicity, and neurotoxicity greatly, which was represented by reduction of reduced glutathione content and the activities of glutathione peroxidase, catalase, and superoxide dismutase and elevation of concentrations of nitric oxide and malondialdehyde in renal, hepatic, brain, and heart tissues. In addition, it increased serum levels of urea, creatinine, tumor necrosis factor-alfa, interleukin-1beta and interleukin-6 and serum activities of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, and creatine kinase-MB. However, S. platensis restored normal levels of measured serum parameters, ameliorated MC-LR-induced oxidative damage, and normalized tissue antioxidant biomarkers. In conclusion, SP alleviated MC-induced organ toxicities by mitigating oxidative and nitrosative stress and lipid peroxidation.
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Introduction
The blue-green algae (cyanobacteria) inhabit freshwater, brackish, marine, and terrestrial environments (Hitzfeld et al. 2000; Ward et al. 1998). Their toxins have deleterious effects on humans, animals, and plants (Carmichael 2001; Corbel et al. 2014; Wang et al. 2021). Microcystis aeruginosa (cyanobacteria) produce the most abundant cyanotoxin, microcystin (MC), into freshwater due to extensive anthropogenic eutrophication (Ahmad et al. 2014). MC tolerates high temperatures (up to 300°C), which increases its stability in the aquatic environment (Wannemacher 1989). The exposure of humans and animals to MC occurs through drinking water and eating contaminated vegetables and seafood (Hu et al. 2016; WHO 1998). MC-induced toxic effects have been reported in many countries including Saudi Arabia (Mohamed 2008), Egypt (Mohamed et al. 2003), Poland (Romanowska-Duda et al. 2002), China (Chen and Xie 2005), Japan (Yokoyama and Park 2002), and Brazil (Azevedo et al. 2002). They are considered a potent neuro- and hepatotoxin (Hu et al. 2016; Jiang et al. 2013) that can cause liver damage by inhibiting protein phosphates 1 and 2A (Humpage and Falconer 1999; Campos and Vasconcelos 2010). MC reaches the hepatocytes through the biliary system because of its high affinity to serine/threonine-containing enzyme phosphatases, which leads to disruption in signaling pathways and cytoskeleton integrity (Xu et al. 2013; Basha et al. 2008). Moreover, the prolonged exposure to MC damages the liver (Chen et al. 2009) and promotes carcinogenesis in humans (Xu et al., 2013). It has been implicated in promoting colon (Humpage et al. 2000) and liver tumors (Ito et al. 1997). MC induces its toxicities by inhibiting cellular antioxidant systems and reactive oxygen species (ROS) overproduction (Jiang et al. 2013; Wang et al. 2017). Biodegradation of MC includes physical, chemical, microbiological, and biotechnological methods. Alternative strategies to detoxify MC have become a global research interest (Massey et al. 2018). It has been indicated that reduced glutathione (GSH) plays indispensable roles in the detoxification of MC as it conjugates with MCS in the liver of mice, rats, and aquatic organisms forming MCLR-GSH conjugate (Pflugmacher et al. 1998; Gehringer et al. 2004; Li et al. 2015). Among various MCs, MC-LR is the most studied one (Li et al. 2021).
Spirulina platensis (SP) is a nutritionally enriched filamentous cyanobacterium with many biomedical applications (Khan et al. 2005; Abdel-Daim et al. 2013; Abdel-Daim et al. 2019a; Abdel-Daim et al. 2015). It contains free radical scavenging agents and naturally occurring antioxidants, including phenolic compounds, tocopherol, β-carotene, γ-linolenic acid, and phycocyanin (Khan et al. 2005). In addition, SP and its main constituent, C-phycocyanin, exhibit hepatoprotective, neuroprotective, anti-inflammatory, immunomodulatory, and anticancer action (Reddy et al. 2000; Romay et al. 2003; Khan et al. 2005). They have been reported to improve organ toxicities caused by heavy metals (El-Desoky et al. 2013; Simsek et al. 2009). SP received growing interest due to its safety, high bioavailability, and significant protection against organ toxicities induced by different chemicals and pollutants (Lu et al. 2010; Avdagic et al. 2008; Abdel-Daim et al. 2013; Abdel-Daim et al. 2019a; El-Desoky et al. 2013; Ibrahim and Abdel-Daim 2015).
Therefore, the current work aimed to evaluate SP protective, anti-inflammatory, and antioxidant effects against MC-induced multi-organ toxicities in rats, mainly by examining liver and kidney functions, proinflammatory cytokines, and oxidant/antioxidants status.
Materials and methods
Chemicals
Pure powder of Spirulina platensis was obtained from HerbaForce (UK) and MC-LR was obtained from Sigma-Aldrich (USA). Kits for oxidant/antioxidant marker determination and biochemical assay kits (urea, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were obtained from Biodiagnostics Company (Egypt). Kits for LDH (lactate dehydrogenase) were purchased from Randox Lab. Ltd. (UK), while CK-MB (creatine kinase-MB) and CK (creatine kinase) were obtained from StanbioTM (USA). To assess the inflammatory response, kits for TNF-α (tumor necrosis factor-α) was obtained from BioSource Inter. Inc. (USA), while kits for determination of interleukin-6 (IL-6) and interleukin-1β (IL-1β) were purchased from Glory Science Co. Ltd. (USA).
Animals
Forty male Albino Wistar rats with an average weight of 170+20 g were obtained from the Egyptian Organization for Biological Products and Vaccines (VACSERA, Dokki, Giza, Egypt). Rats were accommodated for a week prior to commencement of the experiment under controlled conditions with moderate humidity (60+5%) and light/dark cycle (12:12L/D) and an average temperature of 25 ± 2 °C. Rats were fed ad libitum. The experiment was approved (No:2020089) by The Research Ethical Committee of the Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt. The international regulations were followed to care for laboratory animals to avoid animal suffering.
Experimental protocol
The forty rats were classified randomly into five experimental groups (GI—GV).
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G-I (control): rats received distilled water for 21 days.
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G-II (SP): rats received oral SP (1000 mg/kg BW/day) for 21 days (Abdel-Daim et al. 2013).
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G-III (MC): rats received distilled water orally for 7 days before IP injection with MC-LR (10 μg/kg/day) for 14 days (Arman et al. 2019).
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G-IV (MC-LR-SP-500) group: rats received SP (500 mg/kg/day), orally for 7 days, and then concurrently administrated with MC (10 μg/kg/day, IP) for the subsequent14 days.
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G-V (MC-LR-SP1000) group: rats received SP (1000 mg/kg/day), orally for 7 days, and then concurrently administrated with MC (10 μg/kg/day, IP) for the subsequent14 days.
Collection of blood and tissue samples
Twenty-four hours following the last treatment, rats were anesthetized by isoflurane. Blood specimens were collected by cardiac puncture. The coagulated blood was centrifuged at 3000 rpm for 15 min; serum was collected in aliquots and preserved at −20°C for biochemical assays. Then rats were sacrificed by decapitation, and the heart, brain, liver, and kidney were immediately collected, scrubbed by physiological saline to be free from blood, and homogenized in 0.2M Tris-HCl buffer (ice-cold; pH7.4), and then centrifuged for 30min at (4°C) and 5000 rpm. The resultant supernatants were preserved at −80°C to measure tissue oxidative/antioxidant biomarkers in each tissue.
Biochemical analysis
The activities of and ALT were evaluated according to Reitman and Frankel (1957), while the activity of ALP was evaluated as reported by Tietz et al. (1983). Serum creatinine and urea levels were determined as stated in Larsen (1972 ) and Coulombe and Favreau (1963), respectively, while cardiac biomarkers, CK, CK-MB, and LDH, were estimated as reported by Szasz et al. (1979), Wurzburg et al. (1976), and Babson and Babson (1973), respectively.
Estimation of proinflammatory cytokines
The serum levels of pro-inflammatory markers, TNF-α, IL-1β, and IL-6, were estimated by ELISA kits as reported in manufacturer’s instructions. Using an automatic ELISA reader, the absorbance was determined at 420 nm.
Estimation of the liver, kidney, brain, and heart oxidant/antioxidant markers
The oxidant/antioxidant biomarkers’ levels were estimated in the homogenates of the liver, kidney, heart, and brain tissues. For nitrosative stress, nitric oxide (NO) concentrations were evaluated as reported by Green et al. (1982), and for lipid peroxidation, malondialdehyde (MDA) levels were determined as reported by Mihara and Uchiyama (1978). Further, reduced glutathione (GSH) was determined as reported by Beutler et al. (1963), and glutathione peroxidase (GSH-Px) was evaluated as reported by Paglia and Valentine (1967) in the tissue homogenates, while catalase (CAT) was determined as reported by Aebi (1984) and superoxide dismutase (SOD) was determined as stated in Nishikimi et al. (1972).
Data statistical analysis
For each group, data were presented as mean ± standard error (mean ± SE). Using SPSS (SPSS Inc., version 21.0, USA), the data were statistically analyzed. Homogeneity of variance was checked. The statistical significance was evaluated by applying one-way analysis of variance (ANOVA) followed by Tukey’s test under a probability of 0.05.
Results
Impact of SP treatment on serum biochemical parameters in MC-LR-intoxicated rats
MC-intoxicated rats exhibited a significant increase (P<0.05) in liver enzymes (ALT, 263.3%; AST, 232.5%; and ALP, 236.9%), renal biomarkers (urea 208.7% and creatinine 551.4%), and cardiac enzymes (CK 224.4% and CK-MB 310.9%; LDH 225.7%) compared with normal control rats, while MC-intoxicated rats treated with SP at doses of 500 and 1000 mg/kg were associated with significant improvements (P<0.05) in liver (AST, ALT, and ALP), kidney (urea and creatinine), and cardiac (LDH, CK, and CK-MB) level recording (66.1%, 68.4%, 60.6%, 65.0%, 42.2%, 67.5%, 67.3%, and 52.2% for SP500 mg/kg and 46.8%, 39.7%, 44.4%, 51.4%, 26.0%, 47.0%, 50.8%, and 37.1% for SP1000 mg/kg, respectively) when compared with MC-intoxicated rats (Table 1).
Impact of SP treatment on inflammatory reactions in MC-LR intoxicated rats
There is a significant increase (P<0.05) in serum level of inflammatory markers (TNF-α, IL-1β, and IL-6) in MC-treated rats compared with normal control rats recording (350.8%, 364.9%, and 363.9%, respectively) (Figure 1), while treatment of MC-intoxicated rats using SP at doses of 500 and 1000 mg/kg explained significant decrease (P<0.05) in serum TNF-α, IL-1β, and IL-6 concentration recording (44.5%, 48.0%, and 52.5% for SP 500 mg/kg and 67.5%, 32.7%, and 38.3% for SP1000 mg/kg, respectively) when compared with MC-intoxicated rats (Figure 1).
Effects of SP on oxidant/antioxidant biomarkers in MC-LR intoxicated rats
Liver
MC intoxication explained dramatic increase (P<0.05) in liver NO and MDA concentration recording (263.0% and 209.7%, respectively), and significantly decreased (P<0.05) in SOD (32.8%), CAT (44.3%), GSH (50.8%), and GSH-PX (41.5%) activities, when compared with normal control rats.
On the contrary, handling with SP at doses of 500 and 1000 mg/kg, liver NO and MDA level significantly reduced (P<0.05) recording (56.0% and 70.7% for SP 500 mg/kg group and 43.2% and 55.0% for SP1000 mg/kg group, respectively, when compared with MC-intoxicated rats), while treatment by SP explained significant increase (P<0.05) in antioxidant markers’ (GSH, GSHPX, SOD, and CAT) concentrations (for SP500 mg/kg group: 164.5%, 178.9%, 209.2%, and 174.5%, respectively; while for SP1000 mg/kg group: 206.5%, 235.7%, 279.9%, and 210.6%, respectively, compared with MC-intoxicated rats) (Figure 2). Therefore, SP protected liver tissue against the toxicity of MC and normalized the liver tissue levels of antioxidant biomarkers and oxidative stress.
Kidney
MC intoxication explained significant increase (P<0.05) in kidney NO and MDA concentrations (254.3% and 239.6%, respectively), and significantly decreased (P<0.05) in antioxidant (GSH, GSHPX, CAT, and SOD) activities (45.9%, 30.7%, 29.6%, and 54.4%, respectively), when compared with normal control rats.
On the contrary, treatment using SP at doses of 500 and 1000 mg/kg was associated with significant decrease in renal NO and MDA level (for SP 500 mg/kg group: 74.1% and 63.2%, respectively; for SP1000 mg/kg group: 43.5% and 44.5%, respectively compared with MC-intoxicated rats), while treatment with SP caused significant increase (P<0.05) in kidney antioxidant markers’ (GSH, GSHPX, CAT, and SOD) concentrations (for SP500 mg/kg group: 164.0%, 220.9%, 211.7%, and 131.2%, respectively; while for SP1000 mg/kg group: 212.0%, 316.0%, 318.3, and 174.3%, respectively compared with MC-intoxicated rats) (Figure 3). Therefore, SP protected the kidney tissue against the toxicity of MC and normalized the kidney tissue concentration of antioxidant biomarkers and oxidative stress.
Brain
MC intoxication explained dramatic increase (P<0.05) in brain tissue NO and MDA concentrations (188.9% and 197.9%, respectively), but significantly decreased (P<0.05) in GSH (48.8%), GSH-PX (41.3%), CAT (42.7%), and SOD (51.8%) activities, when compared with normal control rats.
On the contrary, treatment by SP at doses of 500 and 1000 mg/kg significantly decreased brain tissue NO and MDA concentrations (P<0.05) (for SP 500 mg/kg group: 75.5% and 79.9%, respectively; for SP1000 mg/kg group: 53.8% and 59.9%, respectively, compared with MC-intoxicated rats), while recorded significant release (P<0.05) in antioxidant markers’ (GSH, GSHPX, CAT, and SOD) activities (for SP 500 mg/kg group: 176.8%, 139.3%, 148.57, and 145.6, respectively; for SP1000 mg/kg group: 203.9%, 210.1%, 228.9%, and 181.4, respectively, when compared with MC-intoxicated rats) (Figure 4). Therefore, SP protected the brain tissue against MC toxicity and normalized the levels of antioxidant biomarkers and oxidative stress.
Heart
MC intoxication explained significant increase (P<0.05) in heart tissue NO and MDA concentration recording (234.2% and 227% respectively), and significantly decreased (P<0.05) in heart tissue antioxidant (GSH, GSHPX, CAT, and SOD) activities (41.9%, 45.0%, 24.9%, and 41.9%, respectively) when compared with normal control rats.
On the contrary, treatment with SP at doses of 500 and 1000 mg/kg significantly decreased (P<0.05) cardiac tissue NO and MDA concentrations (for SP 500 mg/kg group: 59.8% and 63.8%, respectively; for SP1000 mg/kg group: 44.8% and 46.4%, respectively compared with MC-intoxicated rats). Moreover, significant increase (P<0.05) was recorded in cardiac tissue antioxidant markers’ (GSH, GSHPX, CAT, and SOD) activities (for SP500 mg/kg group: 168.9%, 158.4%, 200%, and 162.9%, respectively; for SP1000 mg/kg group: 218.6%, 214.0%, 377.0%, and 221.5%, respectively, compared with MC-intoxicated rats) (Figure 5). Therefore, SP protected the cardiac tissue against MC toxicity and normalized the cardiac tissue levels of antioxidant biomarkers and oxidative stress.
Discussion
Spirulina platensis (SP) is a food supplement microalga with high nutritional importance and a wide range of biomedical applications. It is rich in potent free radical scavenging agents including proteins, lipids, carbohydrates, essential amino acids, essential fatty acids, C-phycocyanin, β carotene, minerals, and vitamins. Besides the antioxidant activity, Spirulina and its active constituents induce neuroprotective, hepatoprotective, nephroprotective, cardioprotective, immunomodulatory, anti-inflammatory, analgesic, antiaging, and anticancer activities (Abdel-Daim et al. 2013; Abdel-Daim et al. 2019a; Abdel-Daim et al. 2015; Abdelkhalek et al. 2015).
This study estimated the preventive role of SP against MC-LR toxic effects on the liver, kidney, heart, and brain. MC-LR induced significant increases in serum values of ALT, AST, ALP, CPK, CK-MB, LDH, urea, creatinine, TNF-α, IL-1β, and IL-6, tissue NO and MDA, and significant reductions in tissue GSH, GSH-PX, CAT, and SOD indicated a dramatic MC-LR toxicity. These data were in consent with the former reports (Abdel-Daim et al. 2019b; Chen and Xie 2005; Jiang et al. 2013; Lone et al. 2017; Robinson et al. 1991). The liver cells represent the essential target of MC-LR intoxication (Campos and Vasconcelos 2010; Robinson et al. 1991). MC-LR affinity with hepatic serine/threonine-specific protein phosphatases induced MC-hepatotoxicity (Greer et al. 2018). This causes cellular dysfunction, leading to leakage of hepatic enzymes into the bloodstream (Robinson et al. 1991). Strong evidence suggests that oxidative stress is implicated in MC-LR-induced hepatotoxicity (Ahmad et al. 2014; Greer et al. 2018). Further, MC-LR acts as a tumor promoter in the liver and colon (Ito et al. 1997; Humpage et al. 2000).
Due to lipid peroxidation, the cell membrane integrity is lost and LDH has released increasing serum levels (Jovanović et al. 2010; Abdel-Daim et al. 2019b). Through the aerobic glycolysis (along the electron transport chain), there is a decrease in ATP production. The reaction shifts to anaerobic glycolysis increasing lactates and LDH (Lone et al. 2017; Jovanović et al. 2010). The MC possibly affects the electron transport chain (Campos and Vasconcelos 2010; Fischer et al. 2005). In addition to hepatotoxicity, nephrotoxicity, and cardiotoxicity, MC-LR can pass the blood-brain barrier inducing neurotoxicity through oxidative damage and phosphatase inhibition (Hu et al. 2016; Fischer et al. 2005).
Oxidative stress in the biological systems occurs through a sequence of events which include the excessive generation of reactive oxygen species (ROS) and NO, which are freed inside the mammalian body due to exposure to endogenous metabolic processes or exogenous drugs in our environment (Sun 1990). Free radicals cause many degenerative diseases like cardiac disease, cataracts, diabetes, cancer, ageing, and stroke (Yeung et al. 2019; Sies et al. 2017). Excessive ROS production overcomes the cellular antioxidant defense mechanisms, which has harmful effects on cellular macromolecules inducing lipid peroxidation, DNA damage, mitochondrial dysfunction, protein oxidation, and ATP reduction (Sies et al. 2017; Salzano et al. 2014). Hydroxyl radicals (•OH) attack the cellular membrane causing MDA production, which binds to other cell molecules increasing the damaging effect. Cellular antioxidants as GSH-PX, GSH, and CAT are required; due to the depletion of these antioxidants, large amount of •OH are formed from H2O2 as it shifts to Fenton’s reaction (Sies et al. 2017). In this study, the significant increase in NO and MDA concentrations with reduction of cellular antioxidants, GSH-Px, GSH, CAT, and SOD, in the liver, kidney, heart, and brain tissues suggested implication of oxidative stress in MC-LR-induced toxicity. MC evoked lipid peroxidation, reducing hepatocyte membrane efficiency and efflux of transaminases into blood stream (Abdel-Daim et al. 2019b; Campos and Vasconcelos 2010). MC accumulation in the liver forms hepatic GSH complex (MC-GSH) as a part of its detoxification process; this leads to GSH exhaustion that is necessary for GSH-PX recycling through hydrolysis of hydrogen peroxide to water (Nordberg and Arnér 2001; Greer et al. 2018).
The oxidative stress and excessive ROS production initiate the intracellular cascade signaling which enhances proinflammatory cytokines expression (Salzano et al. 2014). The current data revealed that MC-LR elevated serum TNF-α, IL-1β, and IL-6 levels because it might induce oxidative stress in the tissues of the liver, kidney, heart, and brain. These data highlighted that the inflammatory reaction might be due to oxidative damage, which was in line with previous findings (Ahmad et al. 2014; Lone et al. 2017). Interestingly, MC could contaminate many SP products, which cannot be ignored as many human beings consume SP on a regular basis as a food supplement (Jiang et al. 2008).
Spirulina platensis supplementation at doses of 500 and 1000 mg/kg significantly decreased the serum injury biomarkers, in addition, lipid peroxidation, as well as it protected liver, kidney, cardiac, and cerebral tissues. SP normalized the elevated activities of serum LDH, CK, and CK-MB and decreased the TIL-induced lipid peroxidation and oxidative stress in a dose-dependent manner (Ibrahim and Abdel-Daim 2015). SP decreases serum concentrations of ALT, AST, ALP, uric acid, urea, and creatinine in deltamethrin-treated animals. In addition, it reduces deltamethrin-induced lipid peroxidation and oxidative stress (Abdel-Daim et al. 2013). This is probably due to the inimical effect of SP that contrary to MC induced oxidative damage through improving SOD and CAT activities or by inhibition of NO and MDA besides scavenging of free radicals (the cellular free radicals’ scavengers and endogenous enzymatic antioxidant). The SP antioxidant and protective effects may be due to its richness with antioxidant active constituents, like β carotene, C-phycocyanin, proteins, lipids, essential fatty acids, essential amino acids, carbohydrates, minerals, and vitamins that are characterized by anti-inflammatory and potent antioxidant activities (Upasani and Balaraman 2003; Abdel-Daim et al. 2015; Abdelkhalek et al. 2015). Numerous studies explained the cardioprotective, hepatoprotective, and nephroprotective role of SP and its active ingredients in contrary to drugs, chemicals, and xenobiotics (Karadeniz et al. 2008; Ibrahim and Abdel-Daim 2015; Kuriakose and Kurup 2011). Moreover, feeding pregnant rats on SP improves the newborns brain damage (Gargouri et al. 2012).
Pre-treatment with SP markedly alleviated the heavy metals’ (cadmium, lead, and mercury) toxicities in rats and mice. SP protective effects is due to its antioxidant roles that are obvious by the decrease in NO and MDA concentration and the increase in GSH levels and SOD action in hepatic tissue (El-Desoky et al. 2013; Karadeniz et al. 2009; Simsek et al. 2009). Moreover, SP has hepatorenal-protective effects by reduction of the contents of NO, MDA, urea, and creatinine, while it increases GSH concentration and GSH-Px, SOD, and CAT activities that indicate the therapeutic effect of SP contrary to cyclosporine, gentamicin, and cisplatin-induced oxidative stress and nephrotoxicity (Lu et al. 2010; Avdagic et al. 2008; Mohan et al. 2006; Khan et al. 2006; Karadeniz et al. 2008; Abdel-Daim et al. 2019a). Antioxidant properties of SP protect against cerebral ischemia injury (Thaakur and Sravanthi 2010). Further, SP reduces lead-induced neurotoxicity in rats (Gargouri et al. 2012). Therefore, our results confirmed SP must play an essential role in avoiding and curing MC-induced cardiac, neurological, hepatic, and renal damage via its powerful antioxidant activities.
Conclusions
MC-LR intoxication caused a significant elevation in serum biomarkers, proinflammatory cytokines, and lipid peroxidation while it suppressed the activity of the antioxidant enzymes. On the other hand, SP could prevent all these changes and normalize all parameters, especially at high concentration doses via its antioxidant and anti-inflammatory activities, which counteract the oxidative stress and inflammatory cascade induced by MC-LR toxicity.
Availability of data and materials
All data are available from the corresponding author when required.
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Acknowledgements
The authors extend their appreciation to the Deanship of Scientific Research at Jouf University for funding this work through research grant number (40/370).
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This work is funded by the Deanship of Scientific Research at Jouf University through research grant number (40/370).
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Idea and design: M. O. G., M. M. A. F., M. M. A-D
Data collection: M. O. G., M. M. A. F., M. K., M. M. A-D
Data analysis: M. O. G., M. M. A. F., M. K., M. M. A-D
Funding: M. O. G., M. M. A. F., M. K., M. M. A-D
Investigation: M. O. G., M. M. A. F., M. K., M. M. A-D
Methodology: M. O. G., M. M. A. F., M. K., M. M. A-D
Project administration: M. O. G., M. M. A. F., M. M. A-D
Software: M. O. G., M. M. A. F., M. K., M. M. A-D
Supervision: M. O. G., M. M. A-D
Validation: M. O. G., M. M. A. F., M. K., M. M. A-D
Visualization: M. O. G., M. M. A. F., M. K., M. M. A-D
Manuscript draft writing: M. O. G., M. M. A. F., M. K., M. M. A-D
Manuscript revision and editing: M. O. G., M. M. A. F., M. K., M. M. A-D
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The Research Ethical Committee of the Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt, permitted the experimental scheme and animal management (the approval no 2020089). We took all the possible procedures to reduce rat sufferance.
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Germoush, .O., Fouda, M.M.A., Kamel, M. et al. Spirulina platensis protects against microcystin-LR-induced toxicity in rats. Environ Sci Pollut Res 29, 11320–11331 (2022). https://doi.org/10.1007/s11356-021-16481-y
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DOI: https://doi.org/10.1007/s11356-021-16481-y