Fructose-1,6-Bisphosphate Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice and Inhibits the Proliferation of Lung Fibroblasts.

Pulmonary fibrosis is a specific form of interstitial pneumonia. In addition to the idiopathic cause, it may be caused by drugs such as bleomycin (BLM)-used in the treatment of tumors. Fructose-1,6-bisphosphate (FBP) is a high-energy endogenous glycolytic compound that has antifibrotic, anti-inflammatory, and immunomodulatory effects. The aim of this study was to investigate the effects of FBP on both BLM-induced pulmonary fibrosis in mice and in a human embryonic lung fibroblast (MRC-5) culture system. C57BL/6 mice were divided into four groups: control, FBP, BLM, and BLM plus FBP. A single dose of bleomycin (7.5 U/kg) was administered intratracheally, and survival, body weight, Ashcroft score, and histological analysis were evaluated. Pulmonary function and bronchoalveolar lavage fluid (BALF) were also evaluated after a single dose of bleomycin (1.2 U/kg-intratracheally). Treatment with FBP (500 mg/kg) was given on day 0 intraperitoneally. Fibroblasts (MRC-5 cells) were used to access the effect of FBP in vitro. In vivo, FBP increased the survival rate and reduced body weight loss (BLM vs. BLM plus FBP-p < 0.05). FBP also prevented BLM-induced loss of pulmonary function and decreased BALF inflammatory cells, level of fibrosis, and superficial collagen density (p < 0.05). In vitro, FBP (0.62 and 1.25 mM) had inhibitory activity on MRC-5 cells and was able to induce senescence in fibroblasts. These results showed that FBP has the potential of reducing the toxic effects of BLM and may provide supportive therapy for conventional methods used for the treatment of cancer.

Fructose 1,6-Bisphosphate: A Summary of Its Cytoprotective Mechanism.

In clinical and experimental settings, a great deal of effort is being made to protect cells and tissues against harmful conditions and to facilitate metabolic recovery following these insults. Much of the recent attention has focused on the protective role of a natural form of sugar, fructose 1,6-bisphosphate (F16bP). F16bP is a high-energy glycolytic intermediate that has been shown to exert a protective action in different cell types and tissues (including the brain, kidney, intestine, liver and heart) against various harmful conditions. For example, there is much evidence that it prevents neuronal damage due to hypoxia and ischemia. Furthermore, the cytoprotective effects of F16bP have been documented in lesions caused by chemicals or cold storage, in a decrease in mortality during sepsis shock and even in the prevention of bone loss in experimental osteoporosis. Intriguingly, protection in such a variety of targets and animal models suggests that the mechanisms induced by F16bP are complex and involve different pathways. In this review we will discuss the most recent theories concerning the molecular model of action of F16bP inside cells. These include its incorporation as an energy substrate, the mechanism for the improvement of ATP availability, and for preservation of organelle membrane stability and functionality. In addition we will present new evidences regarding the capacity of F16bP to decrease oxidative stress by limiting free radical production and improving antioxidant systems, including the role of nitric oxide in the protective mechanism induced by F16bP. Finally we will review the proposed mechanisms for explaining its anti-inflammatory, immunomodulatory and neuroprotective properties.

Metabonomic profiling in studying anti-osteoporosis effects of strontium fructose 1,6-diphosphate on estrogen deficiency-induced osteoporosis in rats by GC/TOF-MS.

A novel strontium salt compound strontium fructose 1, 6-diphosphate (FDP-Sr) has been proved to have highly effective for bone loss via dual effects of stimulating bone formation and suppressing bone absorption. In the present study, metabolomic approach was used to identify and study potential biomarkers associated with the effect and safety of FDP-Sr. The metabolomic profiles of bone loss induced by estrogen deficiency in a rat model was described to attain a system-level map of the shift on the metabolic response in plasma using GC/TOF-MS, after FDP-Sr was orally administered at the dose of 110 mg/kg/day for the prevention and 220 mg/kg/day for the treatment. Meanwhile, bone turnover biomarkers and bone mineral density were investigated to identify the specific changes of potential anti-osteoporosis effects of FDP-Sr. The differences in metabolic profiles between osteoporosis rats and FDP-Sr treated rats were well observed by the partial least squares-discriminant analysis (PLS-DA) to the MS spectra. Some metabolites including homocysteine, arachidonic acid, alanine, and hydroxyproline, which significantly changed during osteoporosis progression could be effectively reversed after FDP-Sr therapy. Of course some metabolites such as uric acid, glyceric acid, octadecadienoic acid, docosahexaenoic acid, oleic acid, and hexadecanoic acid were not found to reverse significantly after FDP-Sr administration. These results delineated the FDP-Sr effects-related metabolic alterations in the bone loss rats, suggesting that metabonomic analysis could provide helpful information on the new potential biomarkers relating to the mechanism of anti-osteoporosis action and side effects of FDP-Sr against estrogen deficiency induced bone loss.

Strontium fructose 1,6-diphosphate prevents bone loss in a rat model of postmenopausal osteoporosis via the OPG/RANKL/RANK pathway.

AIM: To evaluate the protective effects of strontium fructose 1,6-diphosphate (FDP-Sr), a novel strontium salt that combined fructose 1,6-diphosphate (FDP) with strontium, on bone in an ovariectomy-induced model of bone loss. METHODS: Eighty female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated. Three months later, the rats were assigned to six groups (10 for each): sham-operated, OVX control, OVX+FDP-Sr (110, 220, or 440 mg/kg), or OVX+strontium ranelate (SR, 180 mg/kg). Drugs were administered orally for 3 months. When the treatment was terminated, the following parameters were assessed: bone mineral density (BMD), the biomechanical properties of the femur and lumbar vertebrae, trabecular histomorphology, serum phosphorus, calcium, bone-specific alkaline phosphatase (B-ALP), tartrate-resistant acid phosphatase 5b (TRACP5b), N-telopeptide of type I collagen (NTx) and a series of markers for oxidative stress. Receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) levels in serum were measured using ELISA and their gene expression levels in the bone were measured using R-T PCR. RESULTS: Treatment with FDP-Sr (220 or 440 mg/kg) or SR (180 mg/kg) significantly increased the BMD and improved the bone microarchitecture and bone strength in OVX rats. The treatments also decreased in the levels of H(2)O(2) and MDA, restored the CAT level in serum and bone marrow, increased the serum B-ALP and decreased NTx and TRACP 5b in OVX rats. Treatment with FDP-Sr decreased the RANKL level, and increased the OPG level in serum in a dose-dependent manner. It also significantly down-regulated the RANKL expression and up-regulated OPG expression in bone marrow. CONCLUSION: FDP-Sr may be an effectve treatment for postmenopausal osteoporosis that acts, in part, via a decrease in osteoclastogenesis through the OPG\RANKL\RANK pathway.

Fructose-1,6-bisphosphate reduces the mortality in Candida albicans bloodstream infection and prevents the septic-induced platelet decrease.

Due to the fact that an increased number of patients have experienced bloodstream infections caused by Candida species and the high mortality of this infection, there is a need for a strategy to reduce this scenery. One possible strategy is the use of new drugs, such as fructose-1,6-bisphosphate (FBP), which is a high-energy glycolytic metabolite and has shown to have therapeutic effects in several pathological conditions such as ischemia, shock, toxic injuries, and bacterial sepsis. The aim of this manuscript was to determine the role of FBP in experimental Candida albicans bloodstream infection. We used mice that were divided into three experimental groups: sham (not induced), bloodstream infection (induced with intratracheal instillation of C. albicans) and FBP (bloodstream infection plus FBP 500 mg/kg i.p.). Blood was taken for assessment of complete hematological profile and cytokine assay (IL-6 and MCP-1). Results of the study demonstrated that mortality decreased significantly in groups that received FBP. All cytokine and hematological indexes of FBP group were similar to bloodstream infection group with exception of platelets count. FBP significantly prevented the decrease in platelets. Taken together, our results demonstrate that FBP prevented the mortality in C. albicans bloodstream infection.

Fructose-1,6-bisphosphate protects against Zymosan-induced acute lung injury in mice.

It has been previously showed that fructose-1,6-bisphosphate (FBP) has anti-inflammatory and immunomodulatory effects on several experimental inflammation models. However, the effects and mechanism of FBP on Zymosan-induced acute lung injury (ALI) in mice had not been tested. In this study, our aim was to assess the anti-inflammatory activities of FBP on Zymosan-induced ALI. We found that in vivo treatment with FBP (500 mg/kg i.p.) markedly decreased the nitric oxide (NO) levels in the lungs and significantly reduced bronchoalveolar lavage fluid total cell and neutrophil counts and protein exudation after Zymosan challenge. Furthermore, FBP inhibited inducible nitric oxide synthase (iNOS) activities in RAW macrophages. Meanwhile, FBP did not inhibit the cyclooxigenase 2, interleukin-6, and nuclear factor kappa B transcription. Taken together, these results suggest that FBP shows anti-inflammatory effects through inhibiting lung edema, NO, and iNOS activities.

[Strontium fructose 1,6-diphosphate (FDP-Sr) alleviates oligozoospermia induced by multiglycosides of tripterygium wilfordii in rats].

OBJECTIVE: To investigate the effects of strontium fructose 1,6-diphosphate (FDP-Sr) on the multiglycosides of tripterygium wilfordii Hook. f. (GTW)-induced oligozoospermia in male rats. METHODS: Forty SD male rats were randomly divided into 3 groups: model (n=10), FDP-Sr (n=10), and control (n=10). The model rats received intragastric administration of GTW at 30 mg/(kg x d) for 40 days to induce oligozoospermia, the rats of the FDP-Sr group orally administered FDP-Sr at 200 mg/(kg x d) for 30 days after GTW induction, while the control rats given but distilled water. Then we obtained the gonad indexes involving the testis, epididymis, preputial gland and seminal vesicle, and determined the count and motility of epididymal sperm, testicular pathomorphology, serum testosterone level and activities of succinodehydrogenase (SDH), lactate dehydrogenase (LDH) and acid phosphatase (ACP) in the testis. RESULTS: The indexes of the testis and seminal vesicle in the control, model and FDP-Sr groups were (0.71 +/- 0.04) and (0.29 +/- 0.04)%, (0.37 +/- 0.04) and (0.25 +/- 0.05)%, and (0.45 +/- 0.07) and (0.31 +/- 0.06)%, respectively; the epididymal sperm counts were (59.87 +/- 11.28), (11.06 +/- 2.53) and (20.95 +/- 4.98) x 10(6)/ml; the serum testosterone levels were (85.31 +/- 7.41), (65.33 +/- 2.90) and (75.32 +/- 5.34) ng/L; and the activities of ACP, LDH and SDH were (95.64 +/- 19.27), (9574.73 +/- 3 578.06) and (6.39 +/- 1.93) U/g prot, (58.42 +/- 12.38), (4820.77 +/- 1 535.22) and (3.48 +/- 0.91) U/gprot, and (83.74 +/- 21.30), (7649.01 +/- 3 123.02) and (5.59 +/- 1.75) U/g prot. All the parameters above were significantly increased in the FDP-Sr group as compared with the GTW models (P < 0.05). Besides, FDP-Sr treatment significantly alleviated the injury of the testicular seminiferous epithelium. CONCLUSION: FDP-Sr can alleviate GTW-induced oligozoospermia, which is closely related with its improvement of testicular function.

Fructose-1, 6-diphosphate (FDP) as a novel antidote for yellow oleander-induced cardiac toxicity: a randomized controlled double blind study.

BACKGROUND: Cardiac toxicity due to ingestion of oleander plant seeds in Sri Lanka and some other South Asian countries is very common. At present symptomatic oleander seed poisoning carries a mortality of 10% in Sri Lanka and treatment of yellow oleander poisoning is limited to gastric decontamination and atropine administration. The only proven effective antidote is digoxin antibodies but these are not available for routine use because of the high cost. The main objective of this study is to investigate the effectiveness of a new and inexpensive antidote for patients with life threatening arrhythmias due oleander poisoning. METHOD/DESIGN: We set up a randomised double blind clinical trial to assess the effectiveness of Fructose 1, 6 diphosphate (FDP) in acute yellow oleander poisoning patients admitted to the adult medical wards of a tertiary hospital in Sri Lanka. Patients will be initially resuscitated following the national guidelines and eligible patients will be randomised to receive either FDP or an equal amount of normal saline. The primary outcome measure for this study is the sustained reversion to sinus rhythm with a heart rate greater than 50/min within 2 hours of completion of FDP/placebo bolus. Secondary outcomes include death, reversal of hyperkalaemia on the 6, 12, 18 and 24 hour samples and maintenance of sinus rhythm on the holter monitor. Analysis will be on intention-to-treat. DISCUSSION: This trial will provide information on the effectiveness of FDP in yellow oleander poisoning. If FDP is effective in cardiac glycoside toxicity, it would provide substantial benefit to the patients in rural Asia. The drug is inexpensive and thus could be made available at primary care hospitals if proven to be effective. TRIAL REGISTRATION: Current Controlled trial ISRCTN71018309.

Upregulated NADPH oxidase contributes to diabetic testicular complication and is relieved by strontium fructose 1,6-diphosphate.

Diabetes is frequently associated with declining sexual function resulting from oxidative damage. NADPH oxidase is a major resource of reactive oxygen species (ROS) in the testes and is likely related to an activated endothelin-1 (ET-1) system. An activation of NADPH oxidase-ET-1 pathway was hypothesized in diabetic testopathy. We verified the hypothesis and tested if strontium fructose 1,6-diphosphate (FDP-Sr) could relieve these changes in diabetic testis as compared to testosterone propionate (TP) and sildenafil. Diabetes was produced in male Sprague-Dawley rats 8 weeks after a single injection of streptozotocin (STZ), and interventions with testosterone propionate (TP), sildenafil and FDP-Sr were conducted in the last 4 weeks. Blood glucose, testosterone, follicle stimulating hormone (FSH) , luteinizing hormone (LH) and expressions of NADPH oxidase subunits and the ET system were measured. Decreased insulin, FSH, LH and testosterone in serum were found associating with testicular oxidative stress in STZ-injected rats. Additionally, over-expressions of NADPH oxidase p22, p47, p67 subunits and the ET pathway were significant in the diabetic testis relative to normal and were completely abolished by FDP-Sr. Both TP and sildenafil were not beneficial to diabetic testopathy except serum androgen raised by TP. Activated NADPH oxidase and ET system are significant contributing to testis injury and are responded to FDP-Sr only, against both TP and sildenafil, by restoring the testis function and the hypothalamus-pituitary-testis axis. It is due to its extra-energy supply and an antioxidant activity of FDP-Sr.

[Effect of fructose-1,6-diphosphete on myocardial preservation during pulmonary operations].

OBJECTIVE: To investigate the effect of fructose-1,6-diphosphete(FDP) on myocardial preservation in pulmonary operations. METHODS: One hundred and six patients undergoing selective pulmonary lobectomy or segmentectomy were randomly divided into 2 groups with 53 patients each. FDP 200 mg/kg was infused intravenously before anesthesia in the FDP group, while 5% glucose with the same volume was given instead of FDP in the control group. ECGs were monitored from before the anesthesia to 72 h after the operation;the time and type of arrhythmia were recorded. Blood samples were taken before the operation (T0), immediately after the operation(T1), at 24 h(T2),48 h(T3)and 72 h(T(4)) after the operation to determine plasma creatine kinase isoenzyme MB(CK-MB) and cardiac troponin I(cTnI) concentrations. RESULTS: The incidence of arrhythmia in FDP group (35 times) was significantly lower than that in the control group(67 times). The incidence of all types of arrhythmia in the FDP group was also significantly lower than that in the control group. The concentrations of CK-MB and cTnI in the FDP group were significantly lower than those in the control group at T1, T2, T3, and T4. CONCLUSION: FDP is effective for myocardial preservation in pulmonary operations.

Fructose-1,6-diphosphate attenuates acute lung injury induced by lipopolysaccharide in mice.

Fructose-1,6-diphosphate (FDP), a high-energy glycolytic pathway intermediate, is reported to have a salutary effect in endotoxic shock and sepsis, but its underlying mechanism of action in inflammation is incompletely understood. In this study, our aim was to examine the function of FDP on acute lung injury (ALI) induced by lipopolysaccharide (LPS). We found that in vitro pretreatment with FDP remarkably repressed the production of TNF-alpha and IL-6 in murine alveolar macrophages MH-S exposed to LPS. In the mouse model of LPS-induced inflammatory lung injury, intravenous precondition of a single 400 mg/kg dose of FDP resulted in a significant reduction in LPS-mediated extravasation of Evans blue dye albumin, bronchoalveolar lavage leucocyte content, and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration). Furthermore, histopathologic examination indicated that alveolitis with inflammatory cells infiltration and alveolar hemorrhage in the alveolar space was less severe in the FDP-treated mice than in the mice treated by LPS alone at 24 h. Additionally, pretreatment with FDP markedly decreased the transcription of TNF-alpha, IL-6 and inducible NO synthase (iNOS), and suppressed the nuclear translocation of NF-kappaB in lung tissues in response to LPS challenge. These results thus suggested that FDP plays an anti-inflammatory role in LPS-mediated acute lung injury, possibly through abrogation of NF-kappaB activation.

Oral administration of fructose-1,6-diphosphate has anticonvulsant activity.

Recently it has been shown that fructose-1,6-diphosphate (FDP) has dose-dependent anticonvulsant activity in rat models of acute generalized motor seizures induced with chemical convulsants. The present study asked whether FDP also has activity in an epileptic brain after oral administration and activity against non-convulsive seizures. Animals (n = 14) were administered pilocarpine to induce status epilepticus. Several weeks later, these animals had spontaneous seizures and a baseline rate of seizure frequency was determined over a 6-day period. Animals were then continued without treatment (n = 8) or 0.5% FDP was added to the drinking water (n = 6). In animals treated with FDP the seizures completely stopped after 7 days. Removal of FDP from the water resulted in the return of seizure activity in 4 of the 6 animals by 16 days of observation. To induce non-convulsive seizures, animals (n = 6) received a single injection of gamma-butyrolactone (GBL, 100 mg/kg i.p.). All animals had spike-wave activity recorded in the cortex within minutes after GBL administration. Administration of a single injection of FDP (500 g/kg i.p.) had no effect on the baseline cortical activity, nor on the spike-wave activity induced by GBL (n = 5). These experiments suggest that oral administration of FDP may have utility in the treatment of partial or generalized convulsive seizure disorders, but not absence seizures.

Beneficial effects of fructose 1,6-biphosphate on hypothermia-induced reactive oxygen species injury in rats.

The release of reactive oxygen species has been described in hypothermic cells and tissues. Fructose 1,6-biphosphate (F1,6-BP) protects tissue stored at cold temperatures. We study the effect of F1,6-BP in vivo administration on anaesthetized rats exposed to cold stress (4 degrees C chamber for 30 min) and rewarming, to see if it alters cold-induced oxidative injury. Body temperatures show that the animals reached moderate hypothermia (26.80+/-0.62 degrees C) after 30 min of cold exposition. A decrease in mean arterial pressure was found. One group of animals was then rewarmed. Both hypothermia and rewarming increased the production of thiobarbituric acid-reactive substances, an index of lipid peroxidation, and reduced the antioxidant levels of plasmatic sulfhydryl groups, as well as decreasing the enzymatic activities of Cu,Zn-superoxide dismutase (Cu,Zn-SOD), catalase and GSH peroxidase in erythrocytes. Administration of F1,6-BP increased sulfhydryl groups and limited lipid peroxidation in plasma. It furthermore enhanced Cu,Zn-SOD and GSH peroxidase antioxidant activity in erythrocytes and preserved mean arterial pressure. Therefore, F1,6-BP has therapeutic potential based on its ability to reduce free-radical injury resulting from acute cold exposure and rewarming in vivo.

[Protective effect of fructose-1,6-diphosphate against ultrastructural damage in the hippocampus of rats with repeated febrile seizures].

OBJECTIVE: Fructose-1, 6-diphosphate (FDP), serving as a cellular energy substance, has shown its roles in the treatment of hypoxic-ischemic encephalopathy and myocardial damage. The present study aimed at exploring the potentiality of the protective effect of FDP against ultrastructural damage of the hippocampus caused by febrile seizures (FS) in rats. METHODS: Thirty-six 21-day-old male Sprague-Dawley rats were randomly divided into three groups: untreated FS (control), high-dose FDP-treated FS and low-dose FDP-treated FS. FS were induced by hyperthermal bath. Thirty minutes before FS induction, rats in the high-dose and low-dose FDP-treated groups received a peritoneal injection of FDP at a dosage of 50 and 25 mg per 100 g of body weight respectively, whereas the same volume of 0.9% sodium chloride solution were injected to the rats in the control group. Transmission electron microscopy was used to examine the ultrastructural pathologic changes of neurons and organelles as well as the features of synaptic morphological parameters in the hippocampal CA1 area. RESULTS: Neuronal degeneration and necrosis, mitochondria swelling, polyribosomes disaggregation from endoplasmic reticula, and golgiosomes dilation in the hippocampal CA1 area in the two FDP intervention groups were less severe compared with the control group. FDP treatment resulted in significant increases in postsynaptic density thickness (F=12.47, P<0.01), synaptic active zone length (F=14.75, P<0.01) and synaptic interface curvature (F=3.77, P<0.05), as well as a shorter interspace of neural synapses (F=7.29, P<0.01) when compared with the control group. There were no significant differences in the ultrastructural changes between the two FDP treatment groups. CONCLUSIONS: FDP can ameliorate ultrastructural damage in the hippocampus caused by FS in rats. However, further research is warranted for a reasonable and effective dosage of FDP.

Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats.

A variety of observations suggest that decreasing glycolysis and increasing levels of reduced glutathione, generated by metabolism of glucose through the pentose phosphate pathway, would have an anticonvulsant effect. Because fructose-1,6-bisphosphate (F1,6BP) shifts the metabolism of glucose from glycolysis to the pentose phosphate pathway, it was hypothesized to have anticonvulsant activity. The anticonvulsant activity of F1,6BP was determined in rat models of acute seizures induced by pilocarpine, kainic acid, or pentylenetetrazole. The efficacy of F1,6BP was compared with that of 2-deoxyglucose (2-DG; an inhibitor of glucose uptake and glycolysis), valproic acid (VPA), and the ketogenic diet. One hour before each convulsant, Sprague Dawley rats received either saline (as seizure controls), F1,6BP (0.25, 0.5 or 1 g/kg), 2-DG (0.25 or 0.5 g/kg), or VPA (0.3 g/kg). Additional animals received the ketogenic diet (starting at 20 or 60 d old). Time to seizure onset, seizure duration, and seizure score were measured in each group. F1,6BP had dose-dependent anticonvulsant activity in all three models, whereas VPA had partial efficacy. 2-DG was only effective in the pilocarpine model. The ketogenic diet had no effect in these models. F1,6BP was also partially effective when given at the first behavioral seizure after pilocarpine. Administration of sodium lactate, which bypasses the block in the glycolytic pathway, abolished the anticonvulsant activity of 2-DG in the pilocarpine model, but only decreased the efficacy of F1,6BP. These data demonstrate that F1,6BP has significant anticonvulsant efficacy.

Strontium fructose 1,6-diphosphate rescues adenine-induced male hypogonadism and upregulates the testicular endothelin-1 system.

1. Male hypogonadism is a major problem that starts to affect middle-aged men and has adversely effects on human sexual life. The aim of the present study was to investigate the effect of strontium fructose 1,6-diphosphate (FDP-Sr) on male hypogonadism in rats. 2. The pharmacological model of testis dysfunction was created by administration of adenine (200 mg/kg per day, i.g.) for 30 days. Three doses of FDP-Srs (200, 100 and 50 mg/kg per day, i.g.) were administered in parallel with adenine. Finally, mating behaviour index (the mounting latency and the number of mounting events), the total number of spermatozoa and sperm motility, related enzyme function and gene regulation and the mRNA levels of steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage enzyme (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), prepro-endothelin (ET)-1, endothelin-converting enzyme (ECE) and endothelin receptor A (ET(A)) were analysed. 3. The results showed that adenine significantly prolonged the mounting latency and decreased the number of mounting events, markedly reduced the total number of spermatozoa, slowed sperm motility and decreased testicular enzyme activity in the testes. At the mRNA level, adenine significantly downregulated serum testosterone, StAR, P450sc and 3beta-HSD. In parallel, adenine also targeted the ET-1 system, significantly downregulating mRNA levels of prepro-ET-1, ECE and ET(A). Administration of FDP-Sr dose-dependently reversed these effects. 4. In conclusion, adenine-induced testis dysfunction appears to be manifested as loss of sexual function in association with decreased spermatogenesis and reduced mRNA levels of steroidogenesis and the testicular ET-1 system. These abnormalities were significantly restored by FDP-Sr in a dose-dependent manner. These data indicate the possibility of using FDP-Sr to treat male hypogonadism.

Treatment-induced prevention of learning deficits in newborn mice with brain lesions.

Perinatal brain injuries often result in irreversible learning disabilities, which manifest in early childhood. The molecular and cellular mechanisms of these injuries and potential pharmacological treatments are emerging, chiefly from studies in newborn rodents. In newborn mice, experimentally induced lesions can be dramatically reduced by appropriate neuroprotective treatments. However, the early effectiveness of these treatments in preserving cognition remained unknown. Here, we addressed this issue by using intracerebral ibotenate to induce excitotoxic brain lesions in 5-day-old mice (postnatal day 5). On postnatal days 6-7, we tested spontaneous preference for maternal odors, as an index of odor memory, and conditioned preference for an artificial odor previously paired with stroking, as an index of associative learning. Brain-lesioned newborn mice showed normal general status and preference for maternal odors. In contrast, odor conditioning was severely impaired. A previous study showed that fructose 1,6-biphosphate acted as a neuroprotective agent which significantly reduced neocortical lesion size. In the present study, treating the newborn mice with fructose 1,6-biphosphate 15 min before the ibotenate injection reduced neocortical lesion size and restored conditioning. This demonstrates, for the first time, that neuroprotective treatment can protect some features of early cognition.

Fructose-1,6 diphosphate as a protective agent for experimental ischemic acute renal failure.

Cold ischemia time is a risk factor for the development of acute renal failure in the immediate post-transplant period. In this study, we aimed to determine if intravenous fructose-1,6-diphosphate (FDP), given before nephrectomy, attenuates renal cell injury in a cold ischemia model. Male adult Wistar rats were subjected to infusion of either FDP 350 mg/kg (group F, n=6), an equal volume of 0.9% NaCl (group S, n=6), an equal volume/osmolality of mannitol (group M, n=6) or no infusion (group C, n=7). Kidneys were then perfused in situ with Collins solution and nephrectomy was performed. Other kidney slices were stored in Collins solution at 4 degrees C. Adenosine triphosphate (ATP) levels and lactate dehydrogenase (LDH) release were examined at 0, 24, 48 and 72 h. Other slices, obtained after 50 min immersion in Collins solution at 37 degrees C, were frozen for characterization of cytoskeletal preservation using phalloidin-FITC staining. Apical fluorescence intensity of proximal tubule cells, indicative of the F-actin concentration, was measured in a fluorescence microscope interfaced with computer image analysis system. Adenosine triphosphate levels, after up to 72 h of tissue incubation, were higher (P<0.05) in the FDP group when compared to other groups. In addition, LDH release was smaller (P<0.0001) in the FDP group. The F-actin concentration of proximal tubule cells cells was greater in the FDP group (P<0.0001). Results indicate that FDP is a useful tool to increase tissue viability in a rat kidney subjected to cold ischemia, by maintaining ATP cell content, decreasing LDH release and preventing microfilament disruption of proximal tubule cells.

Evaluation of fructose 1,6 diphosphate for salvage of ischemic gracilis flaps in rats.

Fructose 1, 6 diphosphate (FDP), a metabolic intermediate, provides an alternative mechanism to circumvent the rate-limiting step in the Kreb's cycle. This agent has been observed to prevent the effects of ischemia on heart tissue and kidney function and the effects of endotoxic shock. It has been shown conclusively to minimize the adverse effects of ischemia-reperfusion injury in experimental pedicled skin flaps in animals. The present study was done to evaluate the effect of intra-arterial administration of FDP on salvage of ischemic microvascular transfer of gracilis muscle flaps in rats, with the premise that it might prolong the ischemia time of muscle flaps at room temperature, thus increasing chances of flap survival. Irrigation with FDP did not change the quantitative survival of the flaps, but there was qualitative improvement on histologic evaluation and DNA analysis. Decreased inflammatory damage and DNA fragmentation were seen at the 2.5-hr period. Histologic staining for mitochondrial oxygenation in gracilis muscle also showed increased uptake in the FDP-treated group vs. control at the 2.5-hr ischemia period. Further experiments with different modes of FDP administration should be carried out to identify more effective means of amelioration of flap ischemia.

[Antiischemic and antiarrhythmic effect of esafosfina]. / O protivoishemicheskom i antiaritmicheskom deistvii preperata ezafosfina.

Esafosfina, a new preparation based on fructose 1,6-diphosphate, supported the pumping ability of the heart in experiments with a 40-min occlusion followed by 60-min reperfusion of the anterior descending branch of the left coronary artery in anesthetized cats. Esafosfina also exhibited a pronounced antifibrillatory and antiarrhythmic action in anesthetized rats with ventricular fibrillation model.