Neuroprotective effects of daidzein against ifosfamide-induced neurotoxicity in male rats: role of selected inflammatory and apoptotic markers.

Ifosfamide (IFO), an alkylating chemotherapy agent, is known for its association with neurotoxicity and encephalopathy. This trial was designed to evaluate the protective action of daidzein (DZN) against IFO-induced neurotoxicity in male rats by determining the difference in certain inflammatory and apoptotic markers in the brain tissue of rats. Twenty-eight Wistar rats, weighing 120-150 g, were divided into four groups of seven rats: Group 1 (Control) received no treatment; Group 2 was orally administered DZN (100 mg/kg/day) for seven days; Group 3 received a single intraperitoneal (IP) dose of IFO (500 mg/kg); Group 4 received oral DZN (100 mg/kg/day) for one week prior to a single IP dose of IFO on the seventh day. Twenty-four hours post-treatment, serum and brain tissue samples were collected for analysis. The results indicated a significant increase in serum inflammatory markers (TNF-alpha, IL-6, and iNOS) and the anti-inflammatory marker (IL-10), along with elevated caspase-3 enzyme activity in the brain tissue of the IFO-treated group compared to the control group. Conversely, pre-treatment with DZN significantly reduced serum inflammatory markers and caspase-3 levels in tissue. The findings suggest that daidzein has anti-inflammatory and anti-apoptotic properties, potentially offering protection against IFO-induced neurotoxicity in rats.

[Cystinosis in adults: A systemic disease]. / La cystinose chez l'adulte : une maladie systémique.

Cystinosis is a multisystemic autosomal recessive disorder characterized by an intra-lysosomal accumulation of cystine. It is due to a defect of cystine transport through the membrane of the lysosome. The classical infantile form is characterized by a proximal tubulopathy, corneal cystine crystals and progressive renal failure, leading to end stage renal disease before 20 years of age in 90% of cases in historical cohorts. It is the most common cause of Fanconi syndrome in children. Due to recent progress in renal transplantation and to the specific treatment with cysteamine, patients survival improved significantly in the last years and adult nephrologists take care of such patients. However, disease evolution is characterized by other complications: endocrinological (hypothyroidism, diabetes, male hypogonadism), neuromuscular and of the central nervous system. Cysteamine delays the onset of these complications. A multidisciplinary team should take care of these patients, even if the nephrologist remains in first line. Apart from infantile form, there is a juvenile form, with a later onset, and an adult form, which may be only ocular, although renal involvement may be associated. The aim of this revue is to summarize actual knowledge of the disease to provide guidance to adult nephrologist to take care of his patients.

L-Carnitine attenuates ifosfamide-induced carnitine deficiency and decreased intramitochondrial CoA-SH in rat kidney tissues.

BACKGROUND: The effects of L-carnitine on ifosfamide (IFO)-induced Fanconi syndrome have not been studied to date. This study aimed to investigate, on a mechanism basis, whether L-carnitine could prevent the development of IFO-induced Fanconi syndrome in rats. METHODS: Adult male Wistar albino rats were assigned to 1 of 4 treatment groups: group 1 (control) rats were given daily intraperitoneal (i.p.) injections of normal saline for 10 consecutive days; group 2 (L-carnitine) rats were given L-carnitine (200 mg/kg per day, i.p.) for 10 consecutive days. Rats of group 3 (IFO) received normal saline for 5 days, followed by IFO (50 mg/kg per day, i.p.) for 5 consecutive days. Rats of group 4 (IFO plus L-carnitine) received L-carnitine for 5 days before and 5 days concomitant with IFO. RESULTS: Administration of IFO for 5 consecutive days significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion, intramitochondrial acetyl-CoA and thiobarbituric acid reactive substances (TBARS), and significantly decreased total carnitine, intramitochondrial CoA-SH, ATP and ATP/ADP ratio, and reduced glutathione (GSH) in kidney tissues. Administration of L-carnitine to IFO-treated rats resulted in a complete reversal of the increase in serum creatinine, BUN, urinary carnitine excretion and intramitochondrial acetyl-CoA, and of the decrease in total carnitine, intramitochondrial CoA-SH, ATP and GSH, induced by IFO, to the control values. CONCLUSIONS: L-Carnitine prevents the development of IFO-induced Fanconi syndrome by increasing intracellular carnitine content and intramitochondrial CoA-SH, with the consequent improvement in mitochondrial oxidative phosphorylation and energy production, as well as its ability to decrease oxidative stress.

[Nephrotoxicity of ifosfamide with special reference to Fanconi Syndrome]. / Niefrotoksycznosc ifosfamidu ze szczególnym uwzglednieniem zespolu Fanconiego.

UNLABELLED: The article is a case presentation of Fanconi syndrome in a patient treated with high doses of ifosfamide. ifosfamide nephrotoxicity relates to glomerular and tubular disfunction. Tubular disfunction type 2 (Fanconi Syndrome) is observed most often. In this syndrome hypophosphatemia, hyperphosphaturia, glucosuria, polyuria, aminoaciduria, hypokalemia and tubular acidosis are present. The treatment consists of electrolyte supplementation and acidosis reduction. Nephrotoxicity risk factors are: total ifosfamide doses and age under 3 years. Early diagnosis is possible by estimating b2 microglobulin and retinal binding protein. Normally used parameters of renal function are insufficient. MATERIAL AND METHODS: case report - N. W - 13-year-old patient with a skin's tumour was treated in our clinic. Euro Ewing-99 protocol with 100.8 g/m2 of ifosfamide was applied for 18 months. During treatment serum electrolytes, urea, creatinine and creatinine clearance were normal. 6 months after treatment a metastasis in the lung was detected. RESULTS: Fanconi Syndrome symptoms were noticed before introduction of chemotherapy. After treatment with small doses of ifosfamide (4.5 g/m2) the disorders became severe. For this reason, nephrotoxic cytostatics were excluded from further treatment, decreasing its efficiency. CONCLUSIONS: 1. Renal complications of ifosfamide may appear after treatment completion. Monitoring of renal function parameters is necessary during and after treatment. 2. When protocols with cyclophosphamide (less nephrotoxic than ifosfamide) prove to be of similar efficiency, this treatment could be an alternative for patients' with renal disfunction. 3. Patients with completed ifosfamide treatment shall be qualified for repeated chemotherapy carefully due to high-risk of renal disfunction.

Thymoquinone attenuates ifosfamide-induced Fanconi syndrome in rats and enhances its antitumor activity in mice.

The effect of thymoquinone (TQ), the main constituent of the Nigella sativa L. oil, on ifosfamide (IFO)-induced Fanconi syndrome (FS) and its antitumor activity were investigated in rats and mice, respectively. In rats, a daily injection of IFO (50 mg/kg per day, i.p.) for 5 days induced a FS characterized by wasting off glucose, electrolytes and organic acids, along with elevated serum creatinine and urea, as well as decreased creatinine clearance rate. Administration of TQ with the drinking water of rats, (5 mg/kg per day) for 5 days before and during IFO treatment, ameliorated the severity of IFO-induced renal damage. TQ significantly improved IFO-induced phosphaturia, glucosuria, elevated serum creatinine and urea, and significantly normalized creatinine clearance rate. Moreover, TQ significantly prevented IFO-induced renal glutathione (GSH) depletion and lipid peroxide accumulation. In mice bearing Ehrlich ascites carcinoma (EAC) xenograft, TQ (10 mg/kg per day) administered in drinking water significantly enhanced the antitumor effect of IFO (50 mg/kg per day, i.p. on days 1-4 and 15-18). Furthermore, mice treated with IFO in combination with TQ showed less body weight loss and mortality rate compared to IFO single therapy. These observations demonstrate that TQ may improve the therapeutic efficacy of IFO by decreasing IFO-induced nephrotoxicity and improving its antitumor activity.

Taurine attenuates fanconi syndrome induced by ifosfamide without compromising its antitumor activity.

Nephrotoxicity is an important clinical side effect of the chemotherapeutic agent ifosfamide (IFO). Taurine (TAU), an antioxidant amino acid, was used in the present study to evaluate its beneficial effects against the Fanconi syndrome (FS) induced by IFO. The rationale of use of TAU was based on its reported antioxidant effect and the fact that the kidney tends to waste amino acid in IFO-induced FS. Rats received daily injection of IFO (50 mg/kg, IP) for 5 days with or without oral supplementation of 1% TAU in the drinking water for 7 days before IFO and daily thereafter. The results demonstrated that IFO induced a FS characterized by wasting off glucose, electrolytes, and organic acids, along with elevated serum creatinine and urea, and decreased creatinine clearance rate. TAU markedly ameliorated the severity of renal dysfunction induced by IFO, with a significant decrease in total and fractional excretion of Na+, K+, PO4(-3), and glucose, decreased serum creatinine, urea, and albumin, and increased creatinine clearance rate. TAU significantly improved the IFO-induced renal glutathione (GSH) depletion, renal malondialdehyde accumulation, and body weight loss. On the other hand, in Ehrlich ascites carcinoma (EAC)-bearing mice, IFO (50 mg/kg/day, IP on days 1-4 and 15-18) demonstrated antitumor activity as a single agent. No reduction in IFO activity was observed with the supplementation of TAU (1%) in the drinking water. Furthermore, the use of TAU not only maintained high IFO antitumor activity but also was associated with lower toxicity as manifested by less body weight loss and less mortality rate of IFO therapy compared with IFO when given alone. These observations demonstrate that oral supplementation of TAU can protect against IFO-induced renal dysfunction and maintain the antitumor activity of IFO.

Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats.

It has become widely recognized that glycine (Gly) depletion predisposes isolated proximal tubules (PT) to necrotic cell damage induced by diverse insults and that Gly replacement in vitro is highly cytoprotective. However, the effectiveness of supplementation with Gly in vivo, where blood and tissue Gly normally are maintained at high levels, is incompletely defined. Our aim was to assess whether: (a) supplementation of Gly in drinking water of rats would attenuate the proximal tubule damage and the Fanconi syndrome (FS) induced by maleate (Mal), a classical proximal tubule toxin, or ifosfamide (IFO), an antineoplastic drug; and (b) to explore the mechanisms responsible for such effects, since Gly supplementation might be especially beneficial in treating the FS, where the kidney tends to waste amino acids. Rats received daily injection of Mal (2 mmol/kg) for two days without or with oral supplementation of 2% Gly. IFO, 50 mg/kg, was injected daily for five days without or with oral Gly. Control rats were injected with saline, without or with oral Gly. The results demonstrated that both Mal and IFO induced a FS characterized by wasting of amino and organic acids, glucose, and electrolytes, along with elevated plasma creatinine (Crn) and BUN, and decreased Crn clearance rate. Light microscopy revealed a necrotic lesion in the proximal tubules of the Mal group, but no necrosis after IFO. Gly strongly ameliorated the severity of renal necrosis and/or dysfunction induced by Mal or IFO, with significant decreases in total and fractional excretion of Na+, K+, PO4(3-) and glucose, decreased plasma BUN and Crn, and increased Crn clearance. Analysis of freeze-clamped cortical tissue showed substantial depletion of [Gly], [ATP] and [GSH] along with increased GSSG in Mal or IFO groups and correction of [Gly] and [ATP] with Gly supplementation, but no improvement with Gly of reduced gluthatione [GSH] or the ratio of reduced to oxidized gluthatione (GSH/GSSG). 31P-NMR analysis of the renal cortex indicated a decrease in Pi and various membrane phospholipids in Mal and IFO rats and prevention of this damage with Gly. These observations demonstrate that oral supplementation of Gly can provide protection against Mal or IFO-induced renal tubular cell dysfunction and structural damage. The lack of effect on glutathione oxidation and depletion suggests an action distal to toxin uptake and intracellular interactions, which is similar to the characteristics of Gly cytoprotection against diverse insults in vitro. The results also suggest modification by Gly of the primary toxicity of the agents and effects on phospholipid synthesis that could contribute to repair.

Phosphate loading attenuates renal tubular dysfunction induced by maleic acid in the dog.

The metabolic pathogenesis of the complex renal tubular dysfunction of type II renal tubular acidosis and Fanconi's syndrome (RTA II/FS) acutely induced by maleic acid could depend on the occurrence of a positive feedback loop in cells of the proximal renal tubule: impaired mitochondrial oxidation----increased glucose uptake----increased formation and concentration of phosphorylated glycolytic intermediates----limitation on availability of cellular inorganic phosphate----more severely impaired mitochondrial oxidative metabolism. To test this hypothesis we intravenously administered maleic acid both alone and after initiating intravenously administered neutral sodium phosphate, sodium sulfate, or sodium chloride to 10 unanesthetized trained female dogs undergoing water diuresis. We made the following observations: 1) Administration of maleic acid alone predictably induced dose-dependent increments in urine flow (V) and in renal clearance of HCO3-, Na+, K+, and alpha-aminonitrogen and a pronounced increase in the renal clearance and excretion of citrate. 2) Prior phosphate loading, which increased the plasma concentration of phosphate from 2.5 +/- 0.20 to 11.3 +/- 2 mg/dl: a) attenuated the increment in renal clearance of HCO3- by one-half even though the filtered load of bicarbonate was higher by 37%, owing to the higher values of both GFR and plasma bicarbonate concentration that obtained with phosphate loading; b) prevented the increment in renal clearance and excretion of alpha-aminonitrogen; c) significantly attenuated the increments in V and renal clearance of K+; but d) did not affect the increment in renal clearance and excretion of citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of maleate-induced tubular dysfunction by acetoacetate.

Maleate administration produces features that closely resemble the Fanconi syndrome. To determine whether this dysfunction is caused by maleate or its metabolite, maleyl-CoA, which is produced in the succinyl-CoA transferase reaction, the effect of pretreatment with acetoacetate on the maleate dysfunction was tested in rats, Infusion of acetoacetate, 90 mu mol . min-1 . kg body wt-1 protects the kidney from maleate action, whereas administration of propionate, a monocarboxylic anion and CoA-dependent metabolite resembling the anion of acetoacetate, has no effect on maleate-induced renal dysfunction. Maleate (100 mg/kg body wt) alone lowered kidney ATP concentration by 44%, whereas maleate with acetoacetate did not prevent the decreased renal ATP (42%), while glucosuria, phosphaturia, calciuria, and bicarbonaturia were significantly diminished. Similar changes in renal ATP level were observed in rats treated with propionate or propionate and maleate in combination. These experiments demonstrate that maleate per se is not inhibitory but that its metabolite, presumably maleyl-CoA, may inhibit tubule function.