In vivo real-time imaging reveals megalin as the aminoglycoside gentamicin transporter into cochlea whose inhibition is otoprotective.

Aminoglycosides (AGs) are commonly used antibiotics that cause deafness through the irreversible loss of cochlear sensory hair cells (HCs). How AGs enter the cochlea and then target HCs remains unresolved. Here, we performed time-lapse multicellular imaging of cochlea in live adult hearing mice via a chemo-mechanical cochleostomy. The in vivo tracking revealed that systemically administered Texas Red-labeled gentamicin (GTTR) enters the cochlea via the stria vascularis and then HCs selectively. GTTR uptake into HCs was completely abolished in transmembrane channel-like protein 1 (TMC1) knockout mice, indicating mechanotransducer channel-dependent AG uptake. Blockage of megalin, the candidate AG transporter in the stria vascularis, by binding competitor cilastatin prevented GTTR accumulation in HCs. Furthermore, cilastatin treatment markedly reduced AG-induced HC degeneration and hearing loss in vivo. Together, our in vivo real-time tracking of megalin-dependent AG transport across the blood-labyrinth barrier identifies new therapeutic targets for preventing AG-induced ototoxicity.

Protective role of citronellol on antioxidant enzymes and oxidative damage induced by gentamicin in experimental nephrotoxic rats.

BACKGROUND: Gentamicin leads to nephrotoxicity with increasing oxidative stress. In the present research the role of citronellol on oxidative damage induced by gentamicin in nephrotoxic rats was evaluated. METHODS AND RESULTS: Forty-twomale Wistar rats were randomly divided into seven equal groups; healthy control, gentamicin, DMSO, citronellol 50, citronellol 100, citronellol 200 and vitamin E. The animals were anesthetized after 12 days of treatment. Kidney and serum samples were received for biochemical, histological changes, and gene expression assessments. The levels of serum glutathione (GSH), serum and kidney glutathione peroxidase (GPX) and the expression of GPX gene against gentamicin group were increased in citronellol treatment groups. The levels of serum and kidney malondialdehyde (MDA), urine protein, serum creatinine and the gene expression of inflammatory factors including tumor necrosis factor-alpha (TNF-α) and Interleukin 6 (IL-6) against gentamicin group were decreased in these groups. Moreover, recuperation in histological alterations was shown in three groups receiving citronellol compared to the gentamicin group. CONCLUSIONS: Citronellol with its antioxidant and anti-inflammatory properties can decrease kidney damage caused by nephrotoxicity induced by gentamicin.

Calcium channel inhibitor and extracellular calcium improve aminoglycoside-induced hair cell loss in zebrafish.

Aminoglycosides are commonly used antibiotics for treatment of gram-negative bacterial infections, however, they might act on inner ear, leading to hair-cell death and hearing loss. Currently, there is no targeted therapy for aminoglycoside ototoxicity, since the underlying mechanisms of aminoglycoside-induced hearing impairments are not fully defined. This study aimed to investigate whether the calcium channel blocker verapamil and changes in intracellular & extracellular calcium could ameliorate aminoglycoside-induced ototoxicity in zebrafish. The present findings showed that a significant decreased number of neuromasts in the lateral lines of zebrafish larvae at 5 days' post fertilization after neomycin (20 µM) and gentamicin (20 mg/mL) exposure, which was prevented by verapamil. Moreover, verapamil (10-100 µM) attenuated aminoglycoside-induced toxic response in different external calcium concentrations (33-3300 µM). The increasing extracellular calcium reduced hair cell loss from aminoglycoside exposure, while lower calcium facilitated hair cell death. In contrast, calcium channel activator Bay K8644 (20 µM) enhanced aminoglycoside-induced ototoxicity and reversed the protective action of higher external calcium on hair cell loss. However, neomycin-elicited hair cell death was not altered by caffeine, ryanodine receptor (RyR) agonist, and RyR antagonists, including thapsigargin, ryanodine, and ruthenium red. The uptake of neomycin into hair cells was attenuated by verapamil and under high external calcium concentration. Consistently, the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin was also reduced by verapamil and high external calcium. Significantly, zebrafish larvae when exposed to neomycin exhibited decreased swimming distances in reaction to droplet stimulus when compared to the control group. Verapamil and elevated external calcium effectively protected the impaired swimming ability of zebrafish larvae induced by neomycin. These data imply that prevention of hair cell damage correlated with swimming behavior against aminoglycoside ototoxicity by verapamil and higher external calcium might be associated with inhibition of excessive ROS production and aminoglycoside uptake through cation channels. These findings indicate that calcium channel blocker and higher external calcium could be applied to protect aminoglycoside-induced listening impairments.

Investigation the effects of 2-aminoethoxydiphenyl borate (2-APB) on aminoglycoside nephrotoxicity.

Investigation the protective effect of transient receptor potential channel modulator 2-Aminoethoxydiphenyl Borate (2-APB) on aminoglycoside nephrotoxicity caused by reactive oxygen species, calcium-induced apoptosis and inflammation was aimed. Forty Wistar rats were divided (n=8) as follows: Control group; DMSO group; 2-APB group; Gentamicin group (injected 100 mg/kg gentamicin intramuscularly for 10 days); Gentamicin+ 2-APB group (injected 2 mg/kg 2-APB intraperitoneally, then after 30 minutes 100 mg/kg gentamicin was injected intramuscularly for 10 days). Blood samples were collected for biochemical analyses, kidney tissue samples were collected for light, electron microscopic and immunohistochemical investigations. In gentamicin group glomerular degeneration, tubular dilatation, vacuolization, desquamation of tubular cells and hyaline cast formation in luminal space and leukocyte infiltration were seen. Disorganization of microvilli of tubular cells, apical cytoplasmic blebbing, lipid accumulation, myelin figure like structure formation, increased lysosomes, mitochondrial swelling and disorganization of cristae structures, apoptotic changes and widening of intercellular space were found. TNF-α, IL-6 and caspase 3 expressions were increased. BUN and creatinine concentrations were increased. Increase in MDA levels and decrease in SOD activities were determined. Even though degeneration still continues in gentamicin+2-APB treatment group, severity and the area it occupied were decreased and the glomerular and tubule structures were generally preserved. TNF-α, IL-6, caspase 3 immunoreactivities and BUN, creatinine, MDA concentrations were reduced and SOD activities were increased markedly compared to gentamicin group. In conclusion, it has been considered that 2-APB can prevent gentamicin mediated nephrotoxicity with its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

Ezetimibe protects against Gentamycin-induced ototoxicity in rats by antioxidants, anti-inflammatory mechanisms, and BDNF upregulation.

OBJECTIVE: The threat of hearing loss has become a universal reality. Gentamycin (GM) can lead to ototoxicity and may result in permanent hearing loss. This study aimed to elucidate whether the hypolipidemic drug Ezetimibe (EZE) has a possible underlying mechanism for protecting rats from GM-induced ototoxicity. METHODS AND RESULTS: 30 male Wister albino rats were separated into three groups, ten in each group: control, GM, and GM + EZE. At the end of the experiment, rats underwent hearing threshold evaluation via auditory brainstem response (ABR), carotid artery blood flow velocity (CBV), and resistance (CVR) measurement, in addition to a biochemical assessment of serum malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), hemeOxygenase-1 (HO-1), and tumor necrosis factor-α (TNF-α). Also, real-time PCR was employed to quantify the levels of brain-derived neurotrophic factor (BDNF). Cochlea was also studied via histological and immunohistochemical methods. GM revealed a significant increase in CVR, MDA, NO, and TNF-α and a significant decrease in ABR, CBV, CAT, HO-1, and cochlear BDNF expression. EZE supplementation revealed a significant rise in ARB in addition to CBV and a decline in CVR and protected cochlear tissues via antioxidant, anti-inflammatory, and antiapoptotic mechanisms via downregulating Caspase-3 immunoreaction, upregulating proliferating cellular nuclear antigen (PCNA) immunoreaction, and upregulating of the cochlear BDNF expression. Correlations were significantly negative between BDNF and MDA, NO, TNF-α, COX 2, and caspase-3 immunoreaction and significantly positive with CAT, HO-1, and PCNA immunoreaction. DISCUSSION: EZE can safeguard inner ear tissues from GM via antioxidant, anti-inflammatory, and antiapoptotic mechanisms, as well as upregulation of BDNF mechanisms.

Eucalyptol regulates Nrf2 and NF-kB signaling and alleviates gentamicin-induced kidney injury in rats by downregulating oxidative stress, oxidative DNA damage, inflammation, and apoptosis.

Gentamicin, an aminoglycoside antibiotic, is nowadays widely used in the treatment of gram-negative microorganisms. The antimicrobial, anti-inflammatory, and antioxidant activities of eucalyptol, a type of saturated monoterpene, have been reported in many studies. The aim of this study was to examine the possible effects of eucalyptol on gentamicin-induced renal toxicity. A total of 32 rats were divided into 4 groups; Control (C), Eucalyptol (EUC), Gentamicin (GEN), and Gentamicin + Eucalyptol (GEN + EUC). In order to induce renal toxicity, 100 mg/kg gentamicin was administered intraperitoneally (i.p.) for 10 consecutive days in the GEN and GEN + EUC groups. EUC and GEN + EUC groups were given 100 mg/kg orally of eucalyptol for 10 consecutive days. Afterwards, rats were euthanized and samples were taken and subjected to histopathological, biochemical, immunohistochemical, and real-time PCR examinations. The blood urea nitrogen (BUN) and creatinine (CRE) levels were significantly decreased in the GEN + EUC group (0.76 and 0.69-fold, respectively) compared to the GEN group. The glutathione peroxidase (GPx) and catalase (CAT) activities were significantly increased in the GEN + EUC group (1.35 and 2.67-fold, respectively) compared to the GEN group. In GEN group, Nuclear factor kappa B (NF-kB), Interleukin 1-beta (IL-1ß), Inducible nitric oxide synthase (iNOS), Tumor necrosis factor-α (TNF-α), Caspase-3, 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and Nuclear factor erythroid 2-related factor (Nrf2) expression levels were found to be quite irregular. GEN + EUC group decreased the expressions of NF-kB, IL-1ß, iNOS, TNF-α, Caspase-3, and 8-OHdG (0.55, 0.67, 0.54, 0.54, 0.63 and 0.67-fold, respectively), while it caused increased expression of Nrf2 (3.1 fold). In addition, eucalyptol treatment ameliorated the histopathological changes that occurred with gentamicin. The results of our study show that eucalyptol has anti-inflammatory, antioxidative, antiapoptotic, nephroprotective, and curative effects on gentamicin-induced nephrotoxicity.

Protective effect of inhibiting necroptosis on gentamicin-induced nephrotoxicity.

Necroptosis is defined as a novel programmed cell necrosis that is mediated by receptor interacting serine-threonine protein kinase 1 (RIPK1) and other related signals. Necrosis, apoptosis and inflammation are commonly considered as the leading mechanism in acute kidney injury (AKI) induced by gentamicin (GEN), which is a useful antibiotic for treating the infection of Gram-negative bacterial. However, the necroptosis in the pathogenesis of GEN-induced AKI is unknown. In this study, to investigate the process and function of necroptosis in GEN-induced AKI, NRK-52E and HK-2 cells and SD rats were used as the models. The necroptosis-related proteins, including RIPK1, RIPK3, mixed lineage kinase domain-like (MLKL) and phosphorylated MLKL (p-MLKL), were all increasing time-dependently when GEN was continuously given. By using the RIPK1 inhibitor necrostatin-1 (NEC-1) and RIPK3 inhibitor (CPD42), the GEN-induced toxicity of tubular cells was alleviated. Moreover, it was validated that GEN-induced cell apoptosis and inflammation were attenuated after treating with NEC-1 or CPD42, both in vivo and in vitro. When MLKL was knocked down by siRNA, NEC-1 and CPD42 can not further protect the damage of tubular cells by GEN. Although the using of pan-caspase inhibitor Z-VAD significantly decreased GEN-induced apoptosis, it enhanced necroptosis and slightly promoted the decreased cell viability in GEN-treated cells, with the protective effects weaker than NEC-1 or CPD42. Finally, in vitro minimum inhibitory concentration (MIC) tests and bacteriostatic ring studies showed that NEC-1 did not interfere with the antibiotic effects of GEN. Thus, suppressing necroptosis can serve as a promising strategy for the prevention of GEN-induced nephrotoxicity.

Combined treatment of retinoic acid with olfactory ensheathing cells protect gentamicin-induced SGNs damage in the rat cochlea in vitro.

Hearing is mainly dependent on the function of hair cells (HCs) and spiral ganglion neurons (SGNs) which damage or loss of them leads to irreversible hearing loss. Olfactory ensheathing cells (OECs) are specialized glia that forms the fascicles of the olfactory nerve by surrounding the olfactory sensory axons. The OECs, as a regenerating part of the nervous system, play a supporting function in axonal regeneration and express a wide range of growth factors. In addition, retinoic acid (RA) enhances the proliferation and differentiation of these cells into the nerve. In the present study, we co-cultured human OECs (hOECs) with cochlear SGNs in order to determine whether hOECs and RA co-treatment can protect the repair process in gentamycin-induced SGNs damage in vitro. For this purpose, cochlear cultures were prepared from P4 Wistar rats, which were randomly appointed to four groups: normal cultivated SGNs (Control), gentamicin-lesioned SGNs culture (Gent), gentamicin-lesioned SGNs culture treated with OECs (Gent + OECs) and gentamicin-lesioned SGNs culture co-treated with OECs and RA (Gent + OEC& RA). The expression of a specific protein in SGNs was examined using immunohistochemical and Western blotting technique. TUNEl staining was used to detect cell apoptosis. Here, we revealed that combined treatment of OECs and RA protect synapsin and Tuj-1 expression in the lesioned SGNs and attenuate cell apoptosis. These findings suggest that RA co-treatment can enhance efficiency of OECs in repair of SGNs damage induced by ototoxic drug.

Exogenous glutathione protects against gentamicin-induced acute kidney injury by inhibiting NF-κB pathway, oxidative stress, and apoptosis and regulating PCNA.

This study was designed, for the first time, to examine the possible nephroprotective effects of exogenous glutathione (EGSH) (100 mg/kg, intraperitoneally) on gentamicin-induced acute kidney injury (GM-induced AKI). EGSH reduced renal histopathological changes, inflammatory cell infiltration, and improved renal dysfunction in rats with AKI. EGSH ameliorated GM-induced renal oxidative stress by promoting the renal activities of catalase, glutathione peroxidase, and superoxide dismutase and diminishing renal malondialdehyde and serum nitric oxide levels. Interestingly, EGSH inhibited intrinsic apoptosis by downregulating Bax and caspase-3 and upregulating Bcl2 in the kidney of rats with AKI. EGSH decreased GM-induced inflammatory response as reflected by a remarkable decrease in the protein expressions of NF-κB-p65, IL-6, TNF-α, and iNOS and a considerable diminish in myeloperoxidase activity. Finally, EGSH markedly declined proliferative cell nuclear antigen (PCNA) protein expression in the animals with AKI. In summary, EGSH alleviated AKI in rats intoxicated with GM, partially by inhibiting oxidative stress, NF-κB pathway, and intrinsic apoptosis and regulating PCNA.

Further insights into the impact of rebamipide on gentamicin-induced nephrotoxicity in rats: modulation of SIRT1 and ß-catenin/cyclin D1 pathways.

Gentamicin (GM) is an effective antibiotic administered to treat acute Gram-negative infections. Nevertheless, its clinical application is limited due to nephrotoxicity. Therefore, our research aimed to investigate the potential renoprotective impact of rebamipide (RBM), a gastroprotective drug, on GM-induced kidney damage in rats, as well as putative nephroprotective pathways. RBM was orally administered (100 mg/kg/d for 14 d) commencing 7 d before the administration of GM (100 mg/kg/d, intraperitoneally). Nephrotoxicity was elucidated, and the silent information regulator 1 (SIRT1) and ß-catenin/cyclin D1 pathways were assessed. GM induced a significant elevation in the serum levels of creatinine, blood urea nitrogen (BUN), and kidney injury molecule-1 (KIM-1), as well as the relative kidney index. In addition, GM increased lipid peroxidation and lowered total antioxidant capacity (TAC) level and superoxide dismutase (SOD) activity. GM administration also demonstrated a significant amplification in tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), nuclear factor-κappa B p65 (NF-κB p65), p38 mitogen-activated protein kinase (p38 MAPK), and caspase-3 kidney levels, as well as B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio. Notably, RBM treatment amended all these changes induced by GM. Furthermore, the potential role of SIRT1 and ß-catenin-dependent signaling pathways in GM-induced renal injury was assessed. Our findings showed that GM-treated rats demonstrated a substantial decrease in SIRT1, nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) along with an increase in ß-catenin, forkhead box O-3a (FOXO-3a), and cyclin D1 protein expressions. RMB treatment markedly attenuated the deterioration caused by GM on these pathways. Additionally, RBM alleviated the GM-induced deleterious kidney tissue histopathology. In conclusion, our findings have verified that RBM can halt GM-induced renal injury by partly modulating SIRT1 and ß-catenin pathways.

Potential Protective Effects of Ruta Chalepensis L. Extracts Against Gentamicin-Induced Nephrotoxicity via Reduction on Apoptotic, DNA Damage and Oxidative Stress Markers in Mice.

In this study, the protective effects of Ruta chalepensis L. extracts on the extent of tissue damage in gentamicin-induced nephrotoxicity have been investigated. Ruta chalepensis L. extracts were prepared by subcritical water and ultrasound-assisted organic solvent extraction methods. Protective activity of Ruta chalepensis L. extracts on Gentamicin-induced nephrotoxicity is investigated by apoptotic, DNA damage, oxidative stress markers and evaluating histopathological in kidney tissue of mice. Gentamicin significantly increased Caspase-3 and -8 activities, NO levels, serum creatinine and BUN, while 8-OHdG and MDA levels were significantly decreased with Ruta chalepensis L. extract treatment. In addition, Ruta chalepensis L. extracts treatment significantly increased CAT and SOD activities. Histopathological alterations in Gentamicin group were significantly diminished by application of Ruta chalepensis L. extracts. These results suggest that treatment with Ruta chalepensis L. extracts may ameliorate renal dysfunction and structural damage through the reduction of oxidative stress and apoptosis in the kidney.

Salicylic acid protects gentamicin-induced hepatotoxicity: Study in rabbits.

Gentamicin (GM) is a broadly used antibiotic against severe and life-threatening infections, but its efficacy is restricted by the development of liver toxicity. The present study was designed to evaluate the protective effect of salicylic acid (SA) in gentamicin-induced hepatotoxicity in rabbits. Gentamicin and salicylic acid were given at a dose of 80 mg/kg i.p for twenty days. For this purpose, 24 male albino rabbits were randomly divided into four groups. Group I remained untreated and served as control. Group II was given gentamicin, group III was given gentamicin along with Salicylic acid (SA) and group IV was given only salicylic acid. The degree of hepatoprotection was measured by assessment of body weight, liver weight, absolute liver weight and estimations of plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and direct bilirubin, tissue malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) activities. Significant reduction in the elevated liver weight, plasma levels of AST, ALT, bilirubin and tissue MDA and significant elevation in reduced body weight, SOD and CAT activities were found that confirms the protective role of salicylic acid in gentamicin induced hepatotoxicity.

Nephroprotective effects of Helianthus annuus seeds extract in gentamicin induced nephrotoxic male mice.

Acute kidney injury (AKI) causes a decrease in renal function which leads to failure in balancing electrolyte, fluid and acid-base homoeostasis. AKI is a damaging and life-threatening disorder, but it can be managed if identified earlier. This study aimed to investigate the possible nephroprotective effect of Helianthus annuus seeds extract against gentamicin (GM) induced nephrotoxicity in male mice. The control group (0.5 ml normal saline i.p.,), Gentamycin (GM) group (GM 100 mg/kg i.p), silymarin + GM group (silymarin 50 mg/kg and GM 100 mg/kg i.p.,), H. annuus extract (HAE) and GM, group (HAE 250 mg/kg and GM 100 mg/kg i.p), HAE2 + GM group (HAE2; 500 mg/kg and GM 100 mg/kg i.p) and H. annuus oil (HAO) + GM (HAO 2.5 ml/kg and GM 100 mg/kg i.p). Serum creatinine, urea and blood urea nitrogen (BUN) were significantly (P< 0.001) elevated in the GM group compared to the control group. The elevated level of serum creatinine, urea and BUN were decreased significantly (P<0.001) in groups treated with HAE and HAO extracts compared to the GM group. The kidney histopathological study from the GM group showed tubular necrosis, vacuolation and fibrosis. However, the animal that received HAE and HAO showed no tubular necrosis and vacuolation. Only mild inflammation was observed compared to the GM group. In conclusion, the extract caused marked radical scavenger and protected the kidney from oxidative damage of GM. H. annuus seeds contain strong antioxidant compounds, including flavonoids, phenolic acids, tocopherols and minerals, which could be responsible for the current show.

Glutamine alleviates the renal dysfunction associated with gentamicin-induced acute kidney injury in Sprague-Dawley rats.

Sepsis is a clinical condition caused by an uncontrolled response to an infection, leading to acute kidney injury (AKI) and an increased risk of mortality. Although life support and antibiotic therapy are available, the mortality rate remains high in patients with sepsis. The present study investigated the therapeutic effect of glutamine on gentamicin-induced acute kidney injury in Sprague-Dawley rats. We randomly grouped 24 male rats to the normal control, AKI (control), glutamine 50 mg/kg, and glutamine 500 mg/kg groups. The dose was administered orally for 14 consecutive days. Rats treated with glutamine 500 mg/kg showed changes in systolic blood pressure. Glutamine increased renal blood flow, creatinine clearance, and the levels of potassium, creatinine, blood urea nitrogen, and urine osmolality, while reducing the relative excretion of sodium, potassium, urinary sodium, and plasma blood urea nitrogen and creatinine levels. In our study, glutamine supplementation reduced gentamicin-induced oxidative stress and increased catalase, superoxide dismutase, glutathione peroxidase, and glutathione levels in AKI rats. In addition, glutamine supplementation attenuated the severity of pathological features in this model. Collectively, our results showed that gentamicin has therapeutic potential against gentamicin-induced AKI due to its ability to mitigate the effects of oxidative stress.

Intratympanic Administration of Dieckol Prevents Ototoxic Hearing Loss.

OBJECTIVE: Systemic administration of dieckol reportedly ameliorates acute hearing loss. In this study, dieckol was delivered to the inner ear by the intratympanic route. The functional and anatomic effects and safety of dieckol were assessed using the rat ototoxicity model. MATERIALS AND METHODS: Dieckol in a high-molecular-weight hyaluronic acid vehicle (dieckol+vehicle group) or vehicle without dieckol (vehicle-only group) were randomly delivered into 12 ears intratympanically. Ototoxic hearing loss was induced by intravenous administration of cisplatin, gentamicin, and furosemide. The hearing threshold and surviving outer hair cells (OHC) were enumerated. Biocompatibility was assessed by serial endoscopy of the tympanic membrane (TM), and the histology of the TM and the base of bulla (BB) mucosa was quantitatively assessed. RESULTS: The hearing threshold was significantly better (difference of 20 dB SPL) in the dieckol+vehicle group than in the vehicle-only group. The number of surviving OHCs was significantly greater in the dieckol+vehicle group than in the vehicle-only group. There were no signs of inflammation or infection in the ear. The thickness of the TM and the BB mucosa did not differ between the two groups. CONCLUSION: Intratympanic local delivery of dieckol may be a safe and effective method to prevent ototoxic hearing loss.

Acupuncture Attenuates Ototoxicity Induced by Gentamicin in Mice.

CONTEXT: Presbycusis is age-related, progressive, and symmetrical hearing loss in both ears. Acupuncture can play a vital role in the diagnosis and treatment of deafness, but its functional mechanism is still not entirely clear. OBJECTIVE: The study intended to explore acupuncture's protective effects and mechanism of treatment in addressing ototoxicity induced by gentamicin (GM) in aged mice. DESIGN: The research team designed an animal study, and a mouse model of ototoxicity induced by GM was established. SETTING: The study took place in Nanchong Central Hospital, Sichuan, China. ANIMALS: The animals were 48 male, Kunming mice, with sixteen being three months old and 32 being 18 month old. INTERVENTION: The three-month-old mice were randomly assigned to a control group (n = 8) and a GM group (n = 8). The 18-month-old mice were randomly divided into four groups with eight mice each: a positive control group; a negative control group, the GM group; and two intervention groups, the acupuncture + GM group and the drug + GM group. The GM groups were intraperitoneally injected with 100 mg/kg daily of GM for 10 consecutive days. The acupuncture + GM group received acupuncture, and the drug + GM group was injected intraperitoneally with Genadol. OUTCOME MEASURES: The effects of GM induction and treatment with acupuncture or a drug on the numbers of auditory cochlear hair cells were evaluated via an auditory test and cell staining. A real-time polymerase chain reaction (PCR) was performed for gene detection. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) were measured. RESULTS: The aged mice were susceptible to GM ototoxicity. After acupuncture, the threshold of the auditory brainstem response and the number of cochlear hair cells increased significantly. Acupuncture inhibited oxidative stress via the nuclear factor erythroid-derived factor 2-related factor 2 (NRF2) signaling pathway in the mice. CONCLUSIONS: The data demonstrated that acupuncture can alleviate GM ototoxicity via the NRF2 signaling pathway, providing important support for acupuncture in treatment of GM ototoxicity.

A new active peptide from Neptunea arthritica cumingii exerts protective effects against gentamicin-induced sensory-hair cell injury in zebrafish.

Gentamicin is commonly used for effective treatment of severe Gram-negative bacterial infections. However, its use is being increasingly restricted owing to the ototoxic effects attributed to it. Gentamicin-induced ototoxicity is thought to be related with apoptosis induced by reactive oxygen species (ROS). In this study, we found a novel active peptide from Neptunea arthritica cumingii with otoprotective effects and no significant embryotoxic effects. The combined application of gentamicin and this novel active peptide helped sensory-hair cells to protect themselves from lethal ROS accumulation. This, in turn, reduced the expression of three genes (caspase-3, caspase-9, Bax), and thereby, the sensory-hair cell apoptosis promoted by ROS accumulation upon gentamicin administration. Our findings provided new insights into the prevention of gentamicin-induced hearing loss.

Nephroprotective effect of ferulic acid on gentamicin-induced nephrotoxicity in female rats.

Ferulic acid is a kind of phenolic compound that can be found in various fruits and vegetables. This study aims to investigate the effect of ferulic acid on nephrotoxicity induced by gentamicin (GM). In this study, rats were separated into 4 groups such that each containing 8 randomly selected rats: Control group, Ferulic Acid (FA) group, Gentamicin (GM) group and Gentamicin + Ferulic acid (GM + FA) group. Blood samples were collected after 24 hours following the 8-day trial period, and kidneys were taken out for histopathological evaluation. Serum urea, creatinine, uric acid and LDH analyses were performed in autoanalyzer while Malondialdehyde (MDA), Advanced Oxidized Protein Products (AOPP), Glutathione (GSH), Superoxide dismutase (SOD), Catalase (CAT), Interleukin 6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α) analyses were performed in ELISA, and kidney tissues were also examined histopathologically. Urea (p < .001), creatinine (p < .001), MDA (p < .01), AOPP (p < .001), IL-6 (p < .01) and TNF-α (p < .001) levels were found to be statistically and significantly lowered in GM + FA group when compared to GM group. As a result, ferulic acid has reduced the inflammation in nephrotoxicity induced by GM, causing decreased oxidative stress. In this study, anti-inflammatory features of ferulic acid have come to the forefront rather than the antioxidant features. It can be said that ferulic acid reduces nephrotoxic damage and has protective properties for kidneys.

Protective effects of p-coumaric acid against gentamicin-induced nephrotoxicity in rats.

The most important side effect of gentamicin (GM) is nephrotoxicity. p-Coumaric acid (PCA) is a phenolic compound that scavenges free radicals, reduces fibrosis, and tissue damage. This study investigates the protective effect of PCA on tissue damage and kidney function in gentamicin-induced nephrotoxicity (GIN). Thirty-five rats were separated into five groups and each group contained seven animals: control group, ethanol group, GM group, PCA group, and GM + PCA group. At the end of the seven-day treatment, the rats were sacrificed after blood and kidney tissue samples were taken. While serum urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) levels increased significantly in the GM group compared to the control, they showed a significant decrease in the GM + PCA group compared to the GM. Serum tumor necrosis factor-α (TNF-α) and tissue malondialdehyde (MDA) levels were significantly increased in the GM group compared to the control. While the tissue total oxidant status (TOS) and oxidative stress index (OSI) values of the GM group were significantly higher than the control, they showed a significant decrease in the GM + PCA group compared to the GM. In the histopathological examination, significant tubular necrosis and tubulointerstitial inflammation were detected in the proximal tubules in the GM group compared to the control, while a significant decrease was observed in the severity of these findings in the GM + PCA group compared to the GM. This study shows that PCA has biochemical and histopathological ameliorating effects on GIN in the rat model.

Treatment with human umbilical cord blood serum in a gentamicin-induced nephrotoxicity model in rats.

Sold under the brand name of Garamycin, gentamicin (GM) is an antibiotic in the category of aminoglycoside, that although does have many antibacterial properties, owing to several side effects, its consumption is confined. The current study is aimed at gauging the protective influences of human umbilical cord blood serum (hUCBS) on nephrotoxicity which is induced by GM. In this regard, in the present experimental design, twenty-eight male Wistar rats with the weights of 220 ± 20 g were categorized randomly into 4 groups of seven. The groups included GM (100 mg/kg), control as well as hUCBS at doses of one and two percent together with GM (100 mg/kg) for ten days in an intraperitoneal manner. Blood sampling was collected from the heart directly 24 h after the final injection for obtaining blood serum; the parameters of C-reactive protein (CRP), total oxidant status (TOS), interleukin (IL)-6, lactate dehydrogenase (LDH), total antioxidant capacity (TAC), creatinine (Cr), blood urea nitrogen (BUN), blood serum glutathione (GSH) were gauged in blood serum samples to evaluate renal function. Moreover, for histology, an examination of kidney tissue was performed. In comparison to those of the GM group, in the treatment group, hUCBS significantly decreased the levels of BUN, Cr, LDH, TOS, IL-6, and the CRP levels, and significantly increased the TAC and GSH levels. It was revealed that the treatment of the animals with hUCBS culminates in the reduction of GM' toxic impacts on the kidney.