Protective Effect of Opuntia dillenii (Ker Gawl.) Haw. Seed Oil on Gentamicin-Induced Nephrotoxicity: A Biochemical and Histological Analysis.

Opuntia dillenii is a medicinal plant with frequent usage in folk medicine to treat many illnesses. The present study aims to investigate the protective effect of Opuntia dillenii seed oil against gentamicin-induced nephrotoxicity in rats. The animals (rats) were randomly divided into three groups (i) the normal control group treated only with distilled water (10 mL/kg), (ii) the gentamicin group treated with distilled water (10 mL/kg) and received an intraperitoneal injection of gentamicin (80 mg/kg), and (iii) the group treated with the Opuntia dillenii seed oil (2 mL/kg) and also received an intraperitoneal injection of gentamicin (80 mg/kg). The rats received their following treatments for 14 consecutive days orally. Serum urea, creatinine, gamma-glutamyl transferase, albumin, and electrolyte levels were quantified as the markers of acute renal and liver failure. Besides, the kidney and liver relative weight, kidney malondialdehydes, and kidney histological analysis were determined. The results have shown that daily pretreatment with Opuntia dillenii seed oil (2 mL/kg) prevented severe alterations of biochemical parameters and disruptions of kidney tissue structures. In addition, the results of the present study showed for the first time that Opuntia dillenii seed oil reduced renal toxicity in gentamicin-induced nephrotoxicity in rats. Therefore, Opuntia dillenii seed oil may represent a new therapeutic avenue to preserve and protect renal function in gentamicin-treated patients.

Ursodeoxycholic acid abrogates gentamicin-induced hepatotoxicity in rats: Role of NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS pathways.

AIM: The present study focused on the possible underlying protective mechanisms of UDCA against GNT-induced hepatic injury. METHODS: For achieving this goal, adult male rats were allocated into 4 groups: normal control (received vehicle), GNT (100 mg/kg, i.p. for 8 days), UDCA (60 mg/kg, P.O. for 15 days), and GNT + UDCA (received UDCA for 15 days and GNT started from the 7th day and lasted for 8 days). RESULTS: The results revealed that UDCA significantly improved GNT-induced hepatic injury, oxidative stress, apoptosis, and inflammatory response. Interestingly, UDCA inhibited apoptosis by marked down-regulation of the Bax gene, Caspase-3, and cleaved Caspase-3 protein expressions while the level of Bcl-xL gene significantly increased. Moreover, UDCA strongly inhibited the inflammatory response through the down-regulation of both NF-κB-p65 and TNF-α accompanied by IL-10 elevation. Furthermore, the obtained results ended with the restored of mitochondria function that confirmed by electron microscopy. Histological analysis showed that UDCA remarkably ameliorated the histopathological changes induced by GNT. SIGNIFICANCE: UDCA may be a promising agent that can be used to prevent hepatotoxicity observed in GNT treatment. This effect could be attributed to, at least in part, the ability of UDCA to modulate NF-κB-p65/TNF-α, Bax/Bcl-xl/Caspase-3, and eNOS/iNOS signaling pathways.

Boron, a Trace Mineral, Alleviates Gentamicin-Induced Nephrotoxicity in Rats.

The present study was considered to assess the protective effects of boron (B) on gentamicin-induced oxidative stress, proinflammatory cytokines, and histopathological changes in rat kidneys. Rats were split into eight equal groups which were as follows: control (fed with low-boron diet); gentamicin group (100 mg/kg, i.p.); B5, B10, and B20 (5, 10, and 20 mg/kg B, i.p.) groups; gentamicin (100 mg/kg, i.p.) plus B5, B10, and B20 (5, 10, and 20 mg/kg B, i.p.) groups. B was given to rats 4 days before the gentamicin treatment and B administration was completed on the 14th day. Gentamicin administration was started on the 4th day and finished on the 12th day. Gentamicin increased malondialdehyde levels, while reduced glutathione levels in the blood and kidney. Furthermore, superoxide dismutase and catalase activities of erythrocyte were decreased. Besides, serum and kidney nitric oxide and 8-dihydroxyguanidine levels were increased by gentamicin. Additionally, serum levels and kidney mRNA expressions of TNF-α, NFκB, IL-1ß, and IFN-γ were found to be the highest in the gentamicin group. Histopathologically, interstitial hemorrhage and tubular necrosis were detected in the kidneys of the gentamicin group. Nonetheless, B administration reversed gentamicin-induced lipid peroxidation, antioxidant status, and inflammation. In conclusion, B has a preventive effect against gentamicin-induced nephrotoxicity and ameliorates kidney tissues of the rat.

Tauroursodeoxycholic acid attenuates gentamicin-induced cochlear hair cell death in vitro.

Gentamycin is one of the most clinically used aminoglycoside antibiotics which induce intrinsic apoptosis of hair cells. Tauroursodeoxycholic acid (TUDCA) is known as safe cell-protective agent in disorders associated with apoptosis. We aimed to investigate the protective effects of TUDCA against gentamicin-induced ototoxicity. House Ear Institute-Organ of Corti 1(HEI-OC1) cells and explanted cochlear tissue were treated with gentamicin and TUDCA, followed by serial analyses including cell viability assay, hair cell staining, qPCR, ELISA and western blotting to determine the cell damage by the parameters relevant to cell apoptosis and endoplasmic reticulum stress. TUDCA significantly attenuated gentamicin-induced cell damage in cultured HEI-OC1 cells and explanted cochlear hair cells. TUDCA alleviated gentamicin-induced cell apoptosis, supported by the decreased Bax/Bcl2 ratio compared with that of gentamicin treated alone. TUDCA decreased gentamicin-induced nitric oxide production and protein nitration in both models. In addition, TUDCA suppressed gentamicin-induced endoplasmic reticulum stress as reflected by inversing the expression levels of Binding immunoglobulin protein (Bip), CCAAT/-enhancer-binding protein homologous protein (CHOP) and Caspase 3. TUDCA attenuated gentamicin-induced hair cell death by inhibiting protein nitration activation and ER stress, providing new insights into the new potential therapies for sensorineural deafness.

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death.

Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro. Using zebrafish, 72 compounds were identified that either reduced loading of the MET-channel blocker FM 1-43FX, decreased Texas red-conjugated neomycin labeling, or reduced neomycin-induced hair cell death. After testing these 72 compounds, and 6 structurally similar compounds that failed in zebrafish, 13 were found that protected against gentamicin-induced death of OHCs in mouse cochlear cultures, 6 of which are permeant blockers of the hair cell MET channel. None of these compounds abrogated aminoglycoside antibacterial efficacy. By selecting those without adverse effects at high concentrations, 5 emerged as leads for developing pharmaceutical otoprotectants to alleviate an increasing clinical problem.

Effect of Helichrysum plicatum DC. subsp. plicatum ethanol extract on gentamicin-induced nephrotoxicity in rats.

The aim of this study was to evaluate the possible therapeutic or protective effects of Helichrysum plicatum DC. subsp. plicatum ethanol extract (HPE) against gentamicin-induced nephrotoxicity. Thirty-six Sprague Dawley male rats weighing between 200 and 250 g were used as live material. They were formed into six groups containing 6 rats each and were allowed to adapt to laboratory conditions for 7 d. Group I: control, 5% DMSO intraperitoneal (i.p.); Group II: HPE 100 mg/(kg·d) i.p.; Group III: HPE 200 mg/(kg·d) i.p.; Group IV: gentamicin as 80 mg/(kg·d) i.p.; Group V: gentamicin as 80 mg/(kg·d) i.p.+HPE 100 mg/(kg·d) i.p.; and Group VI: gentamicin as 80 mg/(kg·d) i.p.+HPE 200 mg/(kg·d) i.p. for 8 d. Following treatment, serum, liver, and kidney tissues were used to assess blood urea nitrogen (BUN), creatinine, enzymatic and non-enzymatic antioxidants, and lipid peroxidation. Gentamicin significantly increased serum BUN, creatinin, and liver and kidney levels of malondialdehyde (MDA). It also decreased the activity of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Treatment with the HPE 100 mg/kg reversed gentamicin-induced alterations as evidenced by decreased serum BUN and creatinin, liver and kidney oxidant marker, and tubular necrosis as well as by an increase in antioxidant enzymes. It was found that HPE 200 mg/kg significantly increased liver and kidney tissue MDA levels in nephrotoxicity in rats. As a result, these findings support the proposition that HPE in 100 mg/kg dose demonstrates in the kidney and liver as free radicals and scavenger to prevent the toxic effects of gentamicin in both the biochemical and histopathology parameters.

NaHS Protects Cochlear Hair Cells from Gentamicin-Induced Ototoxicity by Inhibiting the Mitochondrial Apoptosis Pathway.

Aminoglycoside antibiotics such as gentamicin could cause ototoxicity in mammalians, by inducing oxidative stress and apoptosis in sensory hair cells of the cochlea. Sodium hydrosulfide (NaHS) is reported to alleviate oxidative stress and apoptosis, but its role in protecting aminoglycoside-induced hearing loss is unclear. In this study, we investigated the anti-oxidant and anti-apoptosis effect of NaHS in in vitro cultured House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and isolated mouse cochlea. Results from cultured HEI-OC1 cells and cochlea consistently indicated that NaHS exhibited protective effects from gentamicin-induced ototoxicity, evident by maintained cell viability, hair cell number and cochlear morphology, reduced reactive oxygen species production and mitochondrial depolarization, as well as apoptosis activation of the intrinsic pathway. Moreover, in the isolated cochlear culture, NaHS was also demonstrated to protect the explant from gentamicin-induced mechanotransduction loss. Our study using multiple in vitro models revealed for the first time, the potential of NaHS as a therapeutic agent in protecting against aminoglycoside-induced hearing loss.

Protective effects of curcumin on acute gentamicin-induced nephrotoxicity in rats.

BACKGROUND: Gentamicin-induced nephrotoxicity is one of the most common causes of acute kidney injury (AKI). The phenotypic alterations that contribute to acute kidney injury include inflammatory response and oxidative stress. Curcumin has a wide range biological functions, especially as an antioxidant. This study was designed to evaluate the renoprotective effects of curcumin treatment in gentamicin-induced AKI. METHODS: Gentamicin-induced AKI was established in female Sprague-Dawley rats. Rats were treated with curcumin (100 mg/kg body mass) by intragastric administration, once daily, followed with an intraperitoneal injection of gentamicin sulfate solution at a dose of 80 mg/kg body mass for 8 consecutive days. At days 3 and 8, the rats were sacrificed, and the kidneys and blood samples were collected for further analysis. RESULTS: The animals treated with gentamicin showed marked deterioration of renal function, together with higher levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in the plasma as compared with the controls. Animals that underwent intermittent treatment with curcumin exhibited significant improvements in renal functional parameters. We also observed that treatment with curcumin significantly attenuated renal tubular damage, apoptosis, and oxidative stress. Curcumin treatment exerted anti-apoptosis and anti-oxidative effects by up-regulating Nrf2/HO-1 and Sirt1 expression. CONCLUSIONS: Our data clearly demonstrate that curcumin protects kidney from gentamicin-induced AKI via the amelioration of oxidative stress and apoptosis of renal tubular cells, thus providing hope for the amelioration of gentamicin-induced nephrotoxicity.

Melatonin prevents gentamicin-induced testicular toxicity and oxidative stress in rats.

This study investigated the protective effects of melatonin (MT) against gentamicin (GM)-induced testicular toxicity and oxidative damage in rats. GM (100 mg kg(-1) ) was injected intraperitoneally (i.p.) to rats for 6 days. MT (15 mg kg(-1) ) was administered i.p. to rats for 6 days at 1 hr after the GM treatment. GM caused a decrease in prostate and seminal vesicle weights, sperm count and sperm motility. Histopathological examination showed various morphological alterations in the testis, characterised by degeneration of spermatogonia/spermatocytes, decrease in the number of early spermatogenic cells and vacuolisation. In addition, an increased malondialdehyde concentration and decreased glutathione content and glutathione reductase, catalase and glutathione-S-transferase activities were found in the testis. In contrast, MT treatment significantly attenuated the testicular toxicity of GM, including decreased reproductive organ weights, sperm count, and sperm motility and increased histopathological alterations. MT also had an antioxidant benefit by decreasing the lipid peroxidative product malondialdehyde and increasing the level of the antioxidant glutathione and the activities of antioxidant enzymes in the testis. These results indicate that MT prevents testicular toxicity induced by GM in rats, presumably due to its potent antioxidant activity, and its ability to inhibit lipid peroxidation, and restore antioxidant enzyme activity.

Effects of Korean red ginseng extract on acute renal failure induced by gentamicin and pharmacokinetic changes by metformin in rats.

AIM OF THE STUDY: Korean red ginseng is one of the best selling dietary supplements and its individual constituents enhance renal function. Acute renal failure (ARF) is a predisposing complication of diabetes mellitus as a result of combination drug therapy. The combination of antibiotic-antidiabetic drugs can entail toxicities and drug interactions because of the antibiotic resistance in patients with severe bacterial infection. Currently, gentamicin-metformin combination therapy is commonly prescribed for treating bacterial infections and diabetes, even though both drugs are mainly excreted via the kidney. Thus, this study was designed to investigate whether a Korean red ginseng extract (KRG) prevents renal impairment and pharmacokinetic changes by metformin in rats with renal failure induced by gentamicin. MATERIALS AND METHODS: The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of metformin were assessed using control (CON), control with Korean red ginseng extract (KRG-CON), acute renal failure induced by gentamicin (ARF), and ARF with Korean red ginseng (KRG-ARF) rats. RESULTS AND CONCLUSIONS: Pharmacokinetic changes of metformin did not occur in KRG-ARF rats because KRG reduce the renal accumulation of gentamicin compared to ARF rats. Thus, KRG seemed to prevent acute renal failure induced by gentamicin treatment.

Screen of FDA-approved drug library reveals compounds that protect hair cells from aminoglycosides and cisplatin.

Loss of mechanosensory hair cells in the inner ear accounts for many hearing loss and balance disorders. Several beneficial pharmaceutical drugs cause hair cell death as a side effect. These include aminoglycoside antibiotics, such as neomycin, kanamycin and gentamicin, and several cancer chemotherapy drugs, such as cisplatin. Discovering new compounds that protect mammalian hair cells from toxic insults is experimentally difficult because of the inaccessibility of the inner ear. We used the zebrafish lateral line sensory system as an in vivo screening platform to survey a library of FDA-approved pharmaceuticals for compounds that protect hair cells from neomycin, gentamicin, kanamycin and cisplatin. Ten compounds were identified that provide protection from at least two of the four toxins. The resulting compounds fall into several drug classes, including serotonin and dopamine-modulating drugs, adrenergic receptor ligands, and estrogen receptor modulators. The protective compounds show different effects against the different toxins, supporting the idea that each toxin causes hair cell death by distinct, but partially overlapping, mechanisms. Furthermore, some compounds from the same drug classes had different protective properties, suggesting that they might not prevent hair cell death by their known target mechanisms. Some protective compounds blocked gentamicin uptake into hair cells, suggesting that they may block mechanotransduction or other routes of entry. The protective compounds identified in our screen will provide a starting point for studies in mammals as well as further research discovering the cellular signaling pathways that trigger hair cell death.

Ethanol extract of Piper longum L. attenuates gentamicin-induced hair cell loss in neonatal cochlea cultures.

Piper longum L. (PL), also as known as long pepper, a well-known spice and traditional medicine in Asia and Pacific islands, has been reported to exhibit wide spectrum activity including antioxidant activity. However, little information is available on its protective effect on gentamicin (GM) induced ototoxicity which is commonly regarded as being mediated by reactive oxygen species and reactive nitrogen species. This study was undertaken to investigate the protective effect of PL ethanol extract on gentamicin-induced hair cell loss in neonatal cochlea cultures. Cochlea cultures from postnatal day 2-3 mice were used for analysis of the protective effects of PL against gentamicin-induced hair cell loss by phalloidin staining. E. coil cultures were used to determine whether PL interferes with the antibiotic activity of GM. Nitric oxide (NO)-scavenging activity of PL was also measured in vitro. GM induced significant dose-dependent hair cell loss in cochlea cultures. However, without interfering with the antibiotic activity of GM, PL showed a significant and concentration-dependent protective effect against GM-induced hair cell loss, and hair cells retained their stereocilia well. In addition, PL expressed direct scavenging activity toward NO radical liberated within solution of sodium nitroprusside. These findings demonstrate the protective effect of PL on GM-induced hair cell loss in neonatal cochlea cultures, and suggest that it might be of therapeutic benefit for treatment of GM-induced ototoxicity.

Simvastatin protects auditory hair cells from gentamicin-induced toxicity and activates Akt signaling in vitro.

BACKGROUND: Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, known as statins, are commonly used as cholesterol-lowering drugs. During the past decade, evidence has emerged that statins also have neuroprotective effects. Research in the retina has shown that simvastatin, a commonly used statin, increases Akt phosphorylation in vivo, indicating that the PI3K/Akt pathway contributes to the protective effects achieved. While research about neuroprotective effects have been conducted in several systems, the effects of statins on the inner ear are largely unknown. RESULTS: We evaluated whether the 3-hydroxy-3-methylglutaryl-coenzyme A reductase is present within the rat cochlea and whether simvastatin is able to protect auditory hair cells from gentamicin-induced apoptotic cell death in a in vitro mouse model. Furthermore, we evaluated whether simvastatin increases Akt phosphorylation in the organ of Corti. We detected 3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA in organ of Corti, spiral ganglion, and stria vascularis by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, we observed a dose-dependent and significant reduction of hair cell loss in organs of Corti treated with simvastatin in addition to gentamicin, as compared to samples treated with gentamicin alone. The protective effect of simvastatin was reversed by addition of mevalonate, a downstream metabolite blocked by simvastatin, demonstrating the specificity of protection. Finally, Western blotting showed an increase in organ of Corti Akt phosphorylation after simvastatin treatment in vitro. CONCLUSION: These results suggest a neuroprotective effect of statins in the inner ear, mediated by reduced 3-hydroxy-3-methylglutaryl-coenzyme A reductase metabolism and Akt activation.

Effect of rosmarinic acid on inhibition of gentamicin induced nephrotoxicity in rats.

The present investigation reports the effect of rosmarinic acid (RA), an antioxidant on gentamicin sulphate (GS)-induced renal oxidative damage in rats. Rosmarinic acid (RA) has been demonstrated to have antioxidant, free radical scavenger and anti-inflammatory effects. Twenty-eight Sprague-Dawley rats were divided in to four equal groups as follows: group 1 (control), group 2 (GS 100 mg/kg/d ip), group 3 (GS 100 mg/kg/d ip+RA 50 mg/kg/d) and group 4 (GS 100 mg/kg/d ip+RA 100 mg/kg/d). Treatments were administrated once daily for 12 days. After 12 days 24h urine was collected, blood was sampled and kidneys were removed. Serum and kidney tissue MDA assessed by thiobarbituric acid. Kidney paraffin sections (5 µm thickness) from the left kidney stained with periodic acid Schiff. Tubular necrosis was studied semiquantitatively and glomerular volume and volume density of proximal convoluted tubule (PCT) estimated stereologically. Kidney homogenize were prepared from right kidney. Serum creatinine, urea and kidney antioxidant enzymes activity were assessed by special kits. Data were compared by SPSS 13 software and Mann-Whitney test at p < 0.05. Co treatment of GS and RA (High dose) significantly decreased serum creatinine, MDA, urea, tubular necrosis (p < 0.05) and increase renal GSH, GPX, CAT, SOD, volume density of PCT and creatinine clearance significantly in comparison with GS group (p < 0.05). Treatment with RA (high dose) maintained serum creatinine, volume density of PCT, renal GSH, GPX, SOD and MDA as the same level as control group significantly (p < 0.05). In conclusion, RA alleviates GS nephrotoxicity via antioxidant activity, increase of renal GSH content and increase of renal antioxidant enzymes activity.

Experimental gentamicin nephrotoxicity and agents that modify it: a mini-review of recent research.

The aminoglycoside antibiotic gentamicin (GM) is still widely used against infections by Gram-positive and Gram-negative aerobic bacteria. Its therapeutic efficacy, however, is limited by renal impairment that occurs in up to 30% of treated patients. The drug may accumulate in epithelial tubular cells causing a range of effects starting with loss of the brush border in epithelial cells and ending in overt tubular necrosis, activation of apoptosis and massive proteolysis. GM also causes cell death by generation of free radicals, phospholipidosis, extracellular calcium-sensing receptor stimulation and energetic catastrophe, reduced renal blood flow and inflammation. Many drugs have been shown to either ameliorate or potentiate GM nephrotoxicity. This article aims at updating the literature that has been published in the past decade on the effects of agents that either ameliorate or augment the nephrotoxicity of this aminoglycoside. Notable among the new ameliorating procedures are gene therapy, such as intravenous cell therapy with serum amyloid A protein-programmed cells, and the use of some novel antioxidant agents and oils of natural origin. These include, for example, green tea, garlic saffron, grape seed extracts as well as sesame and oleanolic oils. Agents that may augment GM nephrotoxicity include indomethacin, cyclosporin, uric acid and the Ca(++) -channel blocker verapamil. Most of the nephroprotective agents mentioned here have not been tested in large controlled clinical trials. Because of their relative safety and effectiveness, antioxidant agents seem to be good candidates for testing in humans.

Extracellular divalent cations modulate aminoglycoside-induced hair cell death in the zebrafish lateral line.

Aminoglycoside antibiotics cause death of sensory hair cells. Research over the past decade has identified several key players in the intracellular cascade. However, the role of the extracellular environment in aminoglycoside ototoxicity has received comparatively little attention. The present study uses the zebrafish lateral line to demonstrate that extracellular calcium and magnesium ions modulate hair cell death from neomycin and gentamicin in vivo, with high levels of either divalent cation providing significant protection. Imaging experiments with fluorescently-tagged gentamicin show that drug uptake is reduced under high calcium conditions. Treating fish with the hair cell transduction blocker amiloride also reduces aminoglycoside uptake, preventing the toxicity, and experiments with variable calcium and amiloride concentrations suggest complementary effects between the two protectants. Elevated magnesium, in contrast, does not appear to significantly attenuate drug uptake, suggesting that the two divalent cations may protect hair cells from aminoglycoside damage through different mechanisms. These results provide additional evidence for calcium- and transduction-dependent aminoglycoside uptake. Divalent cations provided differential protection from neomycin and gentamicin, with high cation concentrations almost completely protecting hair cells from neomycin and acute gentamicin toxicity, but offering reduced protection from continuous (6 h) gentamicin exposure. These experiments lend further support to the hypothesis that aminoglycoside toxicity occurs via multiple pathways in a both a drug and time course-specific manner.

Response of mechanosensory hair cells of the zebrafish lateral line to aminoglycosides reveals distinct cell death pathways.

We report a series of experiments investigating the kinetics of hair cell loss in lateral line neuromasts of zebrafish larvae following exposure to aminoglycoside antibiotics. Comparisons of the rate of hair cell loss and the differential effects of acute versus chronic exposure to gentamicin and neomycin revealed markedly different results. Neomycin induced rapid and dramatic concentration-dependent hair cell loss that is essentially complete within 90 min, regardless of concentration or exposure time. Gentamicin-induced loss of half of the hair cells within 90 min and substantial additional loss, which was prolonged and cumulative over exposure times up to at least 24h. Small molecules and genetic mutations that inhibit neomycin-induced hair cell loss were ineffective against prolonged gentamicin exposure supporting the hypothesis that these two drugs are revealing at least two cellular pathways. The mechanosensory channel blocker amiloride blocked both neomycin and gentamicin-induced hair cell death acutely and chronically indicating that these aminoglycosides share a common entry route. Further tests with additional aminoglycosides revealed a spectrum of differential responses to acute and chronic exposure. The distinctions between the times of action of these aminoglycosides indicate that these drugs induce multiple cell death pathways.

Calcium and neostigmine antagonize gentamicin, but augment clindamycin-induced tetanic fade in rat phrenic nerve-hemidiaphragm preparations.

PURPOSE: A reduction in acetylcholine release induced by gentamicin may limit neostigmine-induced increases in acetylcholine concentration in the neuromuscular junction. An increase in acetylcholine concentration caused by neostigmine and calcium may enhance the use-dependent ion channel block of the nicotinic acetylcholine receptor caused by clindamycin. The purpose of this study was to determine whether calcium and neostigmine antagonize the neuromuscular blockade caused by gentamicin and augment the blockade caused by clindamycin during both single-twitch (0.1 Hz) and tetanic stimulation (50 Hz for 1.9 s). METHODS: Left phrenic nerve-hemidiaphragm preparations (Male Sprague-Dawley rats, 150-250 g) were mounted in Krebs solution. The concentration-response curves of gentamicin and clindamycin were obtained. The reversal effects of treatment with 5 mM calcium or 250 nM neostigmine on the effects of 1.5 mM gentamicin, which caused 72% reduction of single twitch, were studied. The effects of calcium or neostigmine on the effects of clindamycin were studied by examining the shift of the concentration-response curve of clindamycin with pretreatments with these agents. The effective concentrations were determined by a probit model. RESULTS: Calcium antagonized the single-twitch depression and tetanic fade caused by gentamicin more effectively than neostigmine. The effective concentration of 50% maximal effect (EC(50)) values of clindamycin for tetanic fade in the presence of 5 mM calcium or 250 nM neostigmine were reduced by approximately 52%. CONCLUSION: Clindamycin and gentamicin interfere with neuromuscular transmission and cause tetanic fade. Neostigmine and calcium antagonized the neuromuscular blockade caused by gentamicin, but augmented that caused by clindamycin.

Aqueous-ethanolic extract of morel mushroom mycelium Morchella esculenta, protects cisplatin and gentamicin induced nephrotoxicity in mice.

Morchella esculenta (L) Pers. is an excellently edible and delicious morel mushroom found growing in the temperate forests. The mycelium of this mushroom is widely used as a flavouring agent. The current investigation was undertaken to explore the protective effect of the aqueous-ethanol extract of cultured mycelium of M. esculenta against cisplatin and gentamicin induced acute renal toxicity in Swiss albino mice. Cisplatin and gentamicin when administered induced a marked renal failure, characterized by a significant increase in serum urea and creatinine concentrations. Treatment with the extract at 250 and 500mg/kg body weight decreased the cisplatin and gentamicin induced increase in serum creatinine and urea levels. Treatment with the extract also restored the depleted antioxidant defense system. The decreased activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) in the kidneys consequent to cisplatin and gentamicin administration was significantly elevated. The enhanced renal antioxidant defense system also prevented the tissue lipid peroxidation. The experimental results suggest that aqueous-ethanol extract of morel mushroom, M. esculenta mycelium protected cisplatin and gentamicin induced nephrotoxicity possibly by enhancing renal antioxidant system. The findings thus suggest the potential therapeutic use of morel mushroom mycelium as a novel nephroprotective agent.

Schisandrin B Enhances Renal Mitochondrial Antioxidant Status, Functional and Structural Integrity, and Protects against Gentamicin-Induced Nephrotoxicity in Rats.

Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents. In the present study, the effect of long-term Sch B treatment (1-10 mg/kg/d x 15) on gentamicin-induced nephrotoxicity was examined in rats. Sch B treatment protected against gentamicin-induced nephrotoxicity, as evidenced by significant decreases in plasma creatinine and blood urea nitrogen levels. The nephroprotection was associated with the enhancement in renal mitochondrial antioxidant status, as assessed by the level/activity of reduced glutathione, alpha-tocopherol and Mn-superoxide dismutase, as well as the improvement/preservation of mitochondrial functional and structural integrity, as assessed by the extents of ATP generation capacity, malondialdehyde production, Ca2+ loading and cytochrome c release, as well as the sensitivity to Ca2+-induced permeability transition, in control and gentamicin-intoxicated rats. In conclusion, long-term Sch B treatment could enhance renal mitochondrial antioxidant status as well as improve mitochondrial functional and structural integrity, thereby protecting against gentamicin nephrotoxicity.