Intraperitoneal Injection Of Gentamicin Research Articles

Probiotic activity of <i>Bacillus subtilis</i> metabolites in experimentally induced dysbiosis in mice

Scientific relevance. A promising option for dysbiosis correction is the use of metabiotics, products based on metabolites of probiotic microorganisms. During fermentation, Bacillus subtilis bacteria (strains 3H and 1719) produce metabolites that exhibit probiotic properties in vitro. These observations in vitro motivate an in vivo investigation of B. subtilis metabolite effects on colonic mucosal microbiota in mice in experimentally induced dysbiosis and an assessment of the potential of B. subtilis metabolites as metabiotics.Aim. The authors aimed to compare the probiotic activity of B. subtilis 3H and B. subtilis 1719 metabolites and a commercial metabiotic in antibiotic-induced dysbiosis in mice.Materials and methods. The authors induced experimental dysbiosis in BALB/c mice weighing 18–20 g by intraperitoneal injection of gentamicin. For subsequent correction, the test groups received sorbent-bound B. subtilis metabolites, and the comparison group received a commercial metabiotic containing B. subtilis metabolites (VKPM B-2335(3)3) via intragastric injection for 21 days. The quantitative and qualitative analysis of colonic mucosal microbiota included microbial culturing and colony identification by MALDI-TOF mass spectrometry.Results. Antibiotic-induced colonic dysbiosis in mice manifested itself as a decrease in the dominant microbiota and an increase in opportunistic pathogens. After 7 days of metabolite administration, the Lactobacillus population returned to normal in all treatment groups. The mice that received B. subtilis 3H metabolites showed the best results: their Lactobacillus spp. composition corresponded to that of intact animals. The content of Lac+ Escherichia coli returned to 100% in all treatment groups. After 21 days of metabolite administration, the authors observed the elimination of bacteria (Rodentibacter spp., Aerococcus spp.) and fungi (Trichosporon spp., Kazachstania spp.) in the B. subtilis 3H group; Trichosporon spp. (no effect on Kazachstania spp.) in the B. subtilis 1719 group; and Enterococcus spp., Kazachstania spp., and Trichosporon spp. (no effect on Rodentibacter spp. and Aerococcus spp.) in the commercial metabiotic group.Conclusions. Metabolites of B. subtilis strains 3H and 1719 help to restore the diversity and abundance of colonic microbiota in antibiotic-induced dysbiosis. The differences observed in microbiota re-establishment in the treatment groups indicate that there is interstrain variability in the probiotic activity of B. subtilis metabolites.

Bufalin alleviates acute kidney injury by regulating NLRP3 inflammasome-mediated pyroptosis.

Recently, there has been an increasing clinical incidence of acute kidney injury (AKI), which rapidly declines renal function and leads to massive tubular cell necrosis. Pyroptosis is an inflammatory process of cell death that is more rapid than apoptosis, which is accompanied by a massive release of inflammasome activation. In the study, we aim to explore whether Bufalin regulates the AKI through the pyroptosis pathway. We have established gentamicin (GM)-induced AKI animal and cell models to simulate the pathological conditions of kidney injury. The expression of renal injury and pyroptosis-related indicators were detected by western blot. PAS staining and IHC staining were used to analyze renal function. CCK-8 assay was performed to detect cell viability after AKI with different treatments. TUNEL staining, flow cytometry and immunofluorescence assays were performed to measure pyroptosis. After intraperitoneal injection of GM in rats, renal function was significantly decreased, along with a significant increase of damaged and necrotic cells as suggested by renal tubular epithelial tissue sections. In addition, there was an increase in the pyroptosis-related markers expression and pyroptosis-induced cell death. Consistently, studies in vitro found that GM significantly induced pyroptosis and its associated protein expression in NRK52e cells. Whereas, the administration of Bufalin reversed these effects of GM in vivo and in vitro. Further, we found that Nigericin (NLRP3 agonist) could reversed the effects of bufalin on GM-induced pyroptosis. Bufalin attenuates pyroptosis generated AKI by inhibiting NLRP3 inflammasome.

Comparative effects of parsley leaves aqueous extract and ramipril on gentamicin induced nephrotoxicity in rats

BACKGROUND & OBJECTIVE: Rats are commonly used in experimental studies as they have a smaller body size, they are easily available, and their genetic profiles are similar to each other as compared to humans. Kidney pathologies are the result of an imbalance between reactive oxygen species and antioxidants. Parsley aqueous extract is rich in polyphenolic contents and has nephroprotective effects. The objective of this study is to observe the effects of ramipril and parsley leaves aqueous extract in gentamicin induced nephrotoxicity.
 METHODOLOGY: An Experimental study consisting of 40 healthy male albino rats were randomly distributed into two categories after taking samples for baseline values of urea and creatinine: Category 1 consisted of a control group (Group 1) having 10 rats, while category 2 comprised of 30 rats, divided into three experimental groups after being given intraperitoneal injections of gentamicin (80mg/kg) per day. Group 2 was taken as disease control, while group 3 and group 4 were parsley treated and ramipril treated for 28 days, respectively. Biochemical markers (serum urea and creatinine) were done at day 35. SPSS version 22 was applied for Statistical analysis. One-way ANOVA test was used to determine any difference in mean values. Post hoc tuckeys test was applied for multiple comparisons amongst groups. p<0.05 was measured as significant.
 RESULTS: The treatment decreased the levels of serum urea and creatinine in nephrotoxic rats in group 3 (parsley treated group) and group 4 (ramipril treated group) in comparison to group 2. Group 3 had significantly reduced biochemical markers (p<0.05).
 CONCLUSION: Parsley leaves extract significantly reduced the serum urea and creatinine levels as compared to ramipril.

The Amomum tsao-ko Essential Oils Inhibited Inflammation and Apoptosis through p38/JNK MAPK Signaling Pathway and Alleviated Gentamicin-Induced Acute Kidney Injury

The clinical application of gentamicin may lead to acute kidney injury (AKI), and the nephrotoxicity of gentamicin is related to the pathological mechanism of several oxidative and inflammatory cytokines. Plant-derived essential oils have good anti-inflammatory and antioxidant properties. This study aimed to clarify the protective effect of Amomum tsao-ko essential oils (AOs) on gentamicin-induced AKI in rats and its possible mechanism. The rat AKI model was induced by intraperitoneal injection of gentamicin. After 14 days of oral AO treatment, the renal function and pathological changes of the kidney tissues were evaluated, and the level of kidney tissue oxidative stress was detected. The content of inflammatory cytokines was measured by ELISA. The expression of ERK1/2, JNK1/2, p38, NF-κB, caspase-3, and Bax/Bcl-2 proteins were estimated by Western blot analysis. The results showed that taking AO reduced the contents of serum urea and creatinine in AKI rats and improve the pathological changes and oxidative stress of the kidney tissue in rats. At the same time, AO reduced inflammation and apoptosis during AKI by regulating the MAPK pathway. The data show that AO has a protective effect on the kidneys and may be a potential drug for treating kidney injury.

Protective Effect of Honey and Propolis against Gentamicin-Induced Oxidative Stress and Hepatorenal Damages.

Bee products are a promising source of phenolic compounds with strong antioxidant activity. The present study was designed to explore the protective effect of honey, propolis, and their combination on gentamicin-induced oxidative stress and hepatorenal dysfunction. This study was conducted on male Wistar rats by intraperitoneal injections of gentamicin (120 mg/kg BW/day, i.p.) or normal saline (1 ml/kg BW/day, i.p.) for 10 consecutive days. Honey (2 g/kg BW), propolis (100 mg/kg BW), or their combination were given daily by gavage to normal and gentamicin groups. Honey and propolis samples were evaluated for their phytochemical composition and antioxidant capacity. The in vitro investigations showed that the evaluated samples especially propolis extract have high antioxidant power associated with the presence of several phenolic compounds such as flavonoids, flavan-3-ols, hydroxybenzoic acids, hydroxycinnamic acids, and stilbenes, while honey contains only hydroxybenzoic acids and hydroxycinnamic acids. It was also shown that simultaneous treatment with honey or propolis extract alone or in association prevented changes caused by gentamicin administration and improved hepatic and renal functions. Changes caused by gentamicin administration, observed by in vivo experiments, include significant elevation of uric acid, urea, creatinine, and hepatic enzyme levels (ALT, AST, and ALP) and kidney biochemical changes (an increase of urea, uric acid, and creatinine and a decrease of albumin and total protein) as well as remarkable changes of renal and liver oxidative stress markers (CAT, GPx, and GSH) and elevation of MDA levels. Overall, it can be concluded that honey and propolis might be useful in the management of liver and renal diseases induced by xenobiotics.

The Nephroprotective Effect of Zizyphus lotus L. (Desf.) Fruits in a Gentamicin-Induced Acute Kidney Injury Model in Rats: A Biochemical and Histopathological Investigation.

Zizyphus lotus L. (Desf.) (Z. lotus) is a medicinal plant largely distributed all over the Mediterranean basin and is traditionally used by Moroccan people to treat many illnesses, including kidney failure. The nephrotoxicity of gentamicin (GM) has been well documented in humans and animals, although the preventive strategies against it remain to be studied. In this investigation, we explore whether the extract of Zizyphus lotus L. (Desf.) Fruit (ZLF) exhibits a protective effect against renal damage produced by GM. Indeed, twenty-four Wistar rats were separated into four equal groups of six each (♂/♀ = 1). The control group was treated orally with distilled water (10 mL/kg); the GM treated group received distilled water (10 mL/kg) and an intraperitoneal injection of GM (80 mg/kg) 3 h after; and the treated groups received ZLF extract orally at the doses 200 or 400 mg/kg and injected intraperitoneally with the GM. All treatments were given daily for 14 days. At the end of the experiment, the biochemical parameters and the histological observation related the kidney function was explored. ZLF treatment has significantly attenuated the nephrotoxicity induced by the GM. This effect was indicated by its capacity to decrease significantly the serum creatinine, uric acid, urea, alkaline phosphatase, gamma-glutamyl-transpeptidase, albumin, calcium, sodium amounts, water intake, urinary volume, and relative kidney weight. In addition, this effect was also shown by the increase in the creatinine clearance, urinary creatinine, uric acid, and urea levels, weight gain, compared to the rats treated only with the GM. The hemostasis of oxidants/antioxidants has been significantly improved with the treatment of ZLF extract, which was shown by a significant reduction in malondialdehydes levels. Histopathological analysis of renal tissue was correlated with biochemical observation. Chemical analysis by HPLC-DAD showed that the aqueous extract of ZLF is rich in phenolic compounds such as 3-hydroxycinnamic acid, catechin, ferulic acid, gallic acid, hydroxytyrosol, naringenin, p- coumaric Acid, quercetin, rutin, and vanillic acid. In conclusion, ZLF extract improved the nephrotoxicity induced by GM, through the improvement of the biochemical and histological parameters and thus validates its ethnomedicinal use.

Effect of N Acetyl Cysteine and Aqueous Extract of Berberis Lycium Royale Root Bark on Uric Acid of Albino Rats

Background: N acetyl cysteine and Berberis lycium Royale root bark have been used to treat kidney diseases. Objectives: To evaluate the individual and combined effect of N acetyl cysteine and aqueous extract of Berberis lycium Royale root bark in Gentamicin induced nephrotoxicity in rats. Study Design: Randomized control trial. Settings: Islamic International Medical College, Rawalpindi in collaboration with NIH, Islamabad. Duration: 1 month from September 2020 to October 2020. Methodology: Fifty Wister albino rats of 10-12 weeks old were divided into five groups with 10 in each group. Group 1 was normal control given food and water only and remaining 40 were in treatment groups. Nephrotoxicity was induced by intraperitoneal injection of Gentamicin (80mg/kg) for 6 days in group 2, 3, 4 and 5. After induction of nephrotoxicity, Group 3 was administered N acetyl cysteine 140mg/kg per oral, Group 4 was given aqueous extract of Berberis lycium Royale root bark 400 mg/kg per oral and Group 5 was given both N acetyl cysteine 140mg/kg per oral and aqueous extract of Berberis lycium Royale root bark 400 mg/kg per oral for 21 days. Serum uric acid was measured in all groups after 30 days to observe the reversal of renal injury. Results: The results of this study indicate that Group 3, Group 4 and Group 5 showed a decrease in serum uric acid level as compared to Disease Control Group (Group 2). However, Group 5 significantly reduced uric acid (p 0.05). Conclusion: Combined effect of N acetyl cysteine and aqueous extract of Berberis lycium Royale root bark showed improvement in uric acid level in Gentamicin induced nephrotoxicity in rats.

Protective Effects of Co-Treatment With Hydroethanolic Extract of Origanum Vulgare on Gentamicin-Induced Renal Toxicity in Rats

Objective: Renal toxicity and ototoxicity are considered as the main side effects of aminoglycoside antibiotics, such as gentamicin. The present study aimed to investigate the effect of co-treatment by origanum vulgare extract on the gentamicin-induced renal toxicity. Methods: Adult male Wistar rats in the weight range of 200 to 250 grams were randomly assigned into four groups (n = 8): control, renal toxicity (with the intraperitoneal injection of gentamicin [100 mg/kg/day], for eight days), co-treatment with OV extract and gentamicin vehicle (with the intraperitoneal injection of normal saline and OV extract gavage [40 mg/kg], for eight days), co-treatment with OV ethanolic extract (with the intraperitoneal injection of gentamicin [100 mg/kg/day] and OV extract gavage [40 mg/kg]), for eight days. The amount of urea, creatinine, sodium, potassium, and osmolality were measured in the plasma and urine samples. The left kidney was used for the histological study and the right kidney was used to measure MDA and FRAP. Results: treatment with OV ethanolic extract significantly decreased the blood concentrations of creatinine, urea, the absolute excretion of sodium, the fractional excretion of sodium and potassium, and MDA, compared with the renal toxicity group. Besides, co-treatment with ethanolic extract of origanum Vulgare significantly increased creatinine clearance, urinary osmolality, and FRAP, compared with the renal toxicity group. Conclusion: The oral co-treatment with ethanolic extract of origanum vulgare has a protective effect on gentamicin-induced renal toxicity. This effect can be induced by reducing the oxidative stress caused by free radicals and reducing the amount of lipid peroxidation caused by gentamicin.

Experimental observation on the effect of bone marrow mesenchymal stem cells transplanting CXCR4 over gentamicin ototoxicity

Objective:To observe the survival and migration ability of CXCR4-BMSCs in guinea pig cochlea with gentamycin induced sensorineural hearing loss, and to explore whether SDF-1/CXCR4 axis can mediate bone marrow mesenchymal stem cells (BMSCs) to cochlear homing.Method:BMSCs were isolated and extracted from guinea pigs. A bone marrow mesenchymal stem cell line with overexpression of CXCR4 was established. The animal model of sensorineural deafness was established by intraperitoneal injection of gentamicin［100 mg/(kg·d)］in 50 healthy guinea pigs. The successful deafness animals were randomly divided into three groups(14 rats in each group): sterilizing water group, BMSCs transplantation group and CXCR4-BMSCs transplantation group.Auditory brainstem response(ABR) were performed at 2 weeks and 4 weeks respectively after the tansplantation through cochlear tympanic pathway. The directional homing of the implanted cells in the cochlea was traced by the frozen section fluorescence of the cochlear tissue.Result:The hearing thresholds of the three groups were (91.3±5.2),(90.7±4.8)and (90.9±5.6)dB (SPL) respectively. There was no significant difference among them(P>0.05). In sterile Water group, the hearing thresholds were(89.7±6.4)dB and (89.2±6.7)dB respectively when detected on 2 and 4 weeks after transplantation. There were no significant difference(P>0.05);In BMSCs group, the hearing thresholds were (88.6±5.3)dB(SPL) on 2 weeks and (78.4±7.3)dB(SPL) on 4 weeks after transplantation. In CXCR4-BMSCs group, the hearing thresholds were(75.3±7.8)dB(SPL) on 2 weeks and (62.1±8.4)dB(SPL) on 4 weeks after transplantation. The differences were statistically significant (PThe hearing threshold was (75.3±7.8)dB (SPL) at 2 weeks after operation. The hearing enhancement was about 15 dB, the hearing threshold was (62.1±8.4)dB(SPL) at 4 weeks, the difference was statistically significant(P<0.05).Fluorescence tracing showed that the number of CXCR4-BMSCs homing cells was significantly increased, and showed a cohort like arrangement.Conclusion:The SDF-1/CXCR4 axis plays an important role in the directional homing and differentiation of the cells into the cochlea, which can improve the hearing repair ability of guinea pigs induced by gentamicin induced sensorineural deafness.

Protective effect of hydroalcoholic extract of Pistacia vera against gentamicin-induced nephrotoxicity in rats

Purpose: Pistacia vera is a plant of the family Anacardiaceae found in Central and West Asia. P. vera nut (Pistachio) possess multiple pharmacological effects such as antimicrobial, anti-hyperlipidemia, antioxidant and anti-inflammatory. This study is designed to evaluate the protective effect of the hydroalcoholic extract of pistachio on gentamicin-induced nephrotoxicity in rats.Methods: Nephrotoxicity was induced in rats by intraperitoneal injection of gentamicin (100 mg/kg/day for 7 days). Hydroalcoholic extract of pistachio (10, 50 and 100 mg/kg/p.o) was administered for 7 days. The nephroprotective activity was evaluated by determining creatinine clearance, serum creatinine, urine volume, urine glucose and blood urea nitrogen (BUN) levels. The kidneys were processed for histopathological examinations and all specimens were examined for morphologic parameters involving tubular degeneration, tubular necrosis and tubule interstitial nephritis.Results: Results showed a significant increase in the levels of serum creatinine, urine volume, urine glucose and BUN and decrease of creatinine clearance by gentamicin (GA) administration. Co-administration with pistachio extract showed reduction in the levels of serum creatinine, urine volume, urine glucose and BUN and increase of creatinine clearance in all doses but the most significant alteration was observed in doses of 100 mg/kg. Also, the nephroprotective effect of the GA was confirmed by the histological examination of the kidneys.Conclusion: The study revealed the nephroprotective effect of the hydroalcoholic extract of pistachio. These findings suggest that pistachio treatment may attenuate renal dysfunction and structural damage through the reduction of oxidative stress and inflammation in the kidney.

Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity.

Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFβ1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFβ1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.

Aminoglycoside-Induced Hair Cell Death of Inner Ear Organs Causes Functional Deficits in Adult Zebrafish (Danio rerio)

Aminoglycoside antibiotics, like gentamicin, kill inner ear sensory hair cells in a variety of species including chickens, mice, and humans. The zebrafish (Danio rerio) has been used to study hair cell cytotoxicity in the lateral line organs of larval and adult animals. Little is known about whether aminoglycosides kill the hair cells within the inner ear of adult zebrafish. We report here the ototoxic effects of gentamicin on hair cells in the saccule, the putative hearing organ, and utricle of zebrafish. First, adult zebrafish received a single 30 mg/kg intraperitoneal injection of fluorescently-tagged gentamicin (GTTR) to determine the distribution of gentamicin within inner ear sensory epithelia. After 4 hours, GTTR was observed in hair cells throughout the saccular and utriclar sensory epithelia. To assess the ototoxic effects of gentamicin, adult zebrafish received a single 250 mg/kg intraperitoneal injection of gentamicin and, 24 hours later, auditory evoked potential recordings (AEPs) revealed significant shifts in auditory thresholds compared to untreated controls. Zebrafish were then euthanized, the inner ear fixed, and labeled for apoptotic cells (TUNEL reaction), and the stereociliary bundles of hair cells labeled with fluorescently-tagged phalloidin. Whole mounts of the saccule and utricle were imaged and cells counted. There were significantly more TUNEL-labeled cells found in both organs 4 hours after gentamicin injection compared to vehicle-injected controls. As expected, significantly fewer hair cell bundles were found along the rostral-caudal axis of the saccule and in the extrastriolar and striolar regions of the utricle in gentamicin-treated animals compared to untreated controls. Therefore, as in other species, gentamicin causes significant inner ear sensory hair cell death and auditory dysfunction in zebrafish.

Effect of Stem Cell Factor and Granulocyte-Macrophage Colony-Stimulating Factor-Induced Bone Marrow Stem Cell Mobilization on Recovery from Acute Tubular Necrosis in Rats

Background: Acute tubular necrosis (ATN) is the most common reason for acute kidney injury (AKI), and there is still an absence of effective therapies. Objective: To assess the value of bone marrow cell mobilization by stem cell factor (SCF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy in rats with gentamicin-induced ATN. Methods: ATN was induced in male Sprague–Dawley (SD) rats with five daily high-dose intraperitoneal injections of gentamicin. Subcutaneous injections of SCF and GM-CSF were administered simultaneously and these cytokines were observed on days 2, 5, 10, 17, 24, and 31. Peripheral blood and renal tissue CD34+ cell count, mortality rate, blood urea nitrogen (BUN), serum creatinine (SCr), creatinine clearance rate (CCr), and histopathologic lesion scores were determined. Twelve hours after bone marrow ablation (BMA) by lethal X-ray radiation, specific pathogen-free (SPF) ATN rats were given five daily injections of SCF and GM-CSF. BUN, SCr, and histopathologic lesion scores were evaluated on days 2, 5, and 10. Results: Peripheral blood CD34+ cell count increased significantly in ATN rats between 2 and 10 days after SCF and GM-CSF injection. Mortality was reduced from 34.7% in the ATN group to 18.6% in the ATN+CSF. In addition, cytokines administration significantly decreased SCr and BUN. Moreover, cytokines rapidly ameliorated tubular injury. There was no significant effect on ATN rats after BMA. Conclusions: This study demonstrated that SCF and GM-CSF effectively mobilized bone marrow cells in ATN rats, and cytokines administration partially prevented gentamicin-induced ATN. These results suggest that bone marrow stem cell (BMSC) mobilization may be an effective therapy for ATN.

Protective effect of oleanolic acid on gentamicin induced nephrotoxicity in rats

Oleanolic acid is a molecule of current therapeutic interest. In the present study, oleanolic acid isolated from the cuticular epithelium of Viscum articulatum Burm. f. (Viscaceae) was investigated for its protective effects on gentamicin-induced renal damage in rats. Nephrotoxicity was induced in rats by intraperitoneal injection of gentamicin at a dose of 100 mg/kg/day for 8 days. The effect of Oleanolic acid administered orally at doses 40, 60 and 80 mg/kg/day was assessed biochemically by determination of albumin, urea and creatinine in serum and urine samples and also through histopathological examination of the kidneys. Oleanolic acid protected the rat kidneys from gentamicin-induced nephrotoxicity as evident from a decrease in the serum and urine levels of creatinine, albumin and urea. Oleanolic acid also protected the rat kidneys from histological alterations induced by gentamicin and also improved the glomerular filtration rate. Compared with an earlier report on intraperitoneal administration of oleanolic acid in paracetamol-induced nephrotoxicity in rats, the data show that orally administered oleanolic acid also exerted a nephroprotective effect even in the case of a nephrotoxicant such as gentamicin, which directly deteriorates the kidney function without prior metabolism.

Ethics and Animal Welfare Related to in vivo Pharmacology and Toxicology in Laboratory Animals

Ethics and Animal Welfare Related to <i>in vivo</i> Pharmacology and Toxicology in Laboratory Animals

Elevated Blood Urea Nitrogen (BUN) Levels in Goldfish as an Indicator of Gill Dysfunction

Abstract We examined the effects of copper-induced gill proliferation and gentamicin-induced renal tubular injury on serum creatinine and blood urea nitrogen (BUN) in goldfish Carassius auratus. Fish were given intraperitoneal injections of gentamicin or phospate-buffered saline and kept in either freshwater or copper-treated (100 μg/L) water. Those fish injected with gentamicin showed histologic signs of tubular necrosis. The copper-treated fish had extensive gill epithelial cell hypertrophy and hyperplasia. Serum BUN levels were significantly higher in copper-exposed fish than in freshwater fish, regardless of gentamicin treatment. Serum creatinine levels were unchanged by any of the treatments. This indicates that excretion of nitrogenous wastes across gill membranes is an important part of endogenous toxin removal. However, creatinine serum levels are apparently unaffected by either gill damage or kidney failure. Elevated BUN levels in teleosts may serve as a clinical indication of respiratory and exc...

Role of DL alpha-lipoic acid in gentamicin induced nephrotoxicity.

The effect of DL alpha-lipoic acid on the nephrotoxic potential of gentamicin was examined. Intraperitoneal injection of gentamicin (100 mg/kg/day) to rats resulted in decreased activity of the glycolytic enzymes-hexokinase, phosphoglucoisomerase, aldolase and lactate dehydrogenase. The two gluconeogenic enzymes--glucose-6-phosphatase and fructose-1,6-diphosphatase, the transmembrane enzymes namely the Na+, K(+)-ATPase, Ca(2+)-ATPase, Mg(2+)-ATPase and the brushborder enzyme alkaline phosphatase, also showed decreased activities. This decrease in the activities of ATPases and alkaline phosphatase suggests basolateral and brush border membrane damage. Decreased activity of the TCA cycle enzymes isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH) and malate dehydrogenase (MDH), suggests a loss in mitochondrial integrity. These biochemical disturbances were effectively counteracted by lipoic acid administration. Lipoic acid administration by gastric intubation at two different concentrations (10 mg and 25 mg/kg/day) brought about an increase in the activity of the glycolytic enzymes, ATPases and the TCA cycle enzymes. The gluconeogenic enzymes however showed a further decrease in their activities at both the concentrations of lipoic acid administered. These observations shed light on the nephroprotective action of lipoic acid against experimental aminoglycoside toxicity and the protection afforded at 25 mg/kg/day of lipoic acid was noted to be higher than that at 10 mg level.

Antinociception induced by intraperitoneal injection of gentamicin in rats and mice

Intraperitoneal administration of gentamicin sulfate (5-800 micrograms/kg), but not gentamicin base (23-92 micrograms/kg) produced antinociception in rats and mice, as assessed by the tail-flick, carrageenan-induced articular incapacity tests, and hot-plate tests. The AD50 s in rats (tail-flick test) and mice (hot-plate test) were 11.48 and 147.9 micrograms/kg, respectively, but doses of 200-800 micrograms/kg were required to reduce the hyperalgesia induced in rats by carrageenan. In both species, bell-shaped dose-response curves were obtained, indicating that high doses of gentamicin had little or no effect. Non-effective doses of gentamicin failed to produce a significant increase in morphine antinociception in either rodent species. The possible involvement of N-type voltage-sensitive Ca2+ channels in the mechanism of antinociception induced by gentamicin is considered.

Metronidazole and gentamicin prophylaxis in synergistic aerobe-anaerobe infections in mice.

The efficacy of prophylaxis by intraperitoneal injection of gentamicin, metronidazole or both drugs combined was investigated in a mouse model of mixed infection with Escherichia coli and Bacteroides fragilis. A three dose prophylactic regimen given 12 hourly was studied starting simultaneously with bacterial challenge. Serum antibiotic concentrations lay within the human therapeutic ranges. Metronidazole alone eliminated B. fragilis from the developing infections, but at higher challenge doses the mice developed abscesses which contained E. coli, and mortality was no different from controls. Gentamicin alone eliminated both bacteria and deaths in all infections, but sterile abscesses occurred in two of five animals at the highest challenge dose. Mixed metronidazole + gentamicin abolished all effects of the challenge bacteria, aborting all infections for all challenge doses with no formation of sterile abscesses. It is proposed that, in abdominal surgery, although metronidazole or gentamicin may be effective given alone for low levels of contamination, for higher levels (e.g. colonic surgery) both drugs may be required.

The protective effect of nitrendipine on gentamicin acute renal failure in rats

Aminoglycoside nephrotoxicity was produced in two groups of Fischer rats by intraperitoneal injection of gentamicin, 40 mg/kg/day for 2 weeks. Beginning 3 days prior to, and continuing throughout the 2-week treatment period, one of the groups (control) received the inert vehicle, polyethylene glycol, while the experimental group was given nitrendipine, a calcium channel blocker, in a dose of 25 mg/kg/day by gavage. Both groups received food and water ad libitum. Gentamicin with vehicle caused a marked decrease in inulin clearance (4.9 ml/min/kg) and paraaminohippurate (PAH) extraction (26%), and extensive renal tubular necrosis. In comparison, the nitrendipine-treated rats had a significantly increased clearance (9.8 ml/min/kg) and PAH extraction (48%), and less histopathologic damage. Renal tissue content of gentamicin was not influenced by nitrendipine after 4 days of dosing. Nitrendipine, a diisopyridine derived calcium channel blocker, offers significant functional and histologic protection against aminoglycoside nephrotoxicity in Fischer rats. Its mode of action in this regard is unknown.