Fructose-1,6-diphosphate protects against epileptogenesis by modifying cation-chloride co-transporters in a model of amygdaloid-kindling temporal epilepticus.

Fructose-1,6-diphosphate (FDP) shifts the metabolism of glucose from glycolysis to the pentose phosphate pathway and has anticonvulsant activity in several acute seizure animal models. In the present study, we investigated the anti-epileptogenic effects of FDP in an amygdaloid-kindling seizure model, which is an animal model of the most common form of human temporal lobe epilepsy. We found that 1.0 g/kg FDP slowed seizure progression and shortened the corresponding after-discharge duration (ADD). FDP increased the number of stimulations needed to reach seizure stages 2-5 and prolonged the cumulative ADD prior to reaching stages 3-5. It also shortened staying days and cumulative ADD in stages 4-5. However, it demonstrated no significant protective effect when administered after the animals were fully kindled. In hippocampal neurons, cation-chloride co-transporters (CCCs) are suggested to play interesting roles in epilepsy by modulating γ-aminobutyric acid (GABA)ergic activity through controlling GABAA receptor-mediated reversal potential. We examined the potential link between FDP and the hippocampal expression of two main members of the CCCs: the neuron-specific K(+)-Cl(-)co-transporter 2 (KCC2) and Na(+)-K(+)-Cl(-)co-transporter 1 (NKCC1). FDP inhibited the kindling-induced downregulation of KCC2 expression and decreased NKCC1 expression during the kindling session. Taken together, our data reveal that FDP may have protective activity against epileptogenesis, from partial to generalized tonic-clonic seizures. Furthermore, our findings suggest that the FDP-induced imbalance between KCC2 and NKCC1 expression may be involved in the neuroprotective effect.

N-acetilcisteína e frutose-1, 6-bisfosfato: efeito imunomodulador em cultura de células mononucleares / N-acetilcisteína e frutose-1,6-bisfosfato: efeito imunomodulador em cultura de células mononucleares

INTRODUCTION: Sepsis is a complex syndrome caused by an uncontrolled systemic inflammatory response. Inflammatory cytokines play a pivotal role in septic shock pathogenesis. Therapeutic strategies have been tested in order to modulate the excessive generation or function of sepsis mediators. OBJECTIVE: The objective of the present study was to investigate the therapeutic effect of N-acetylcysteine (NAC) and its association with fructose-1,6-bisphosphate (FBP) on T-lymphocytes proliferation, interleukin-1β (IL-1β) and monocyte chemotactic protein-1 (MCP-1) levels. MATERIAL AND METHODS: Peripheral blood mononuclear cell samples were isolated from healthy individuals. T-lymphocytes were stimulated with phytohemagglutinin for 96 hours and submitted to different concentrations of NAC or NAC associated with FBP. RESULTS: NAC (10 and 15 mM) and NAC (15 mM) associated with FBP reduced T-lymphocytes proliferation. IL-1β levels rose in the presence of both NAC (15 mM) and NAC with FBP (1.25 mM). MCP-1 levels were reduced only by NAC (15 mM) associated with FBP (1.25 mM). CONCLUSION: The results suggest that both NAC itself and NAC associated with FBP inhibit cellular proliferation, acting as potent immunomodulatory agents, which corroborates its use in the treatment of inflammatory diseases.

INTRODUÇÃO: A sepse é uma síndrome complexa causada pela resposta inflamatória sistêmica descontrolada. As citocinas inflamatórias representam papel central na patogênese do choque séptico. Têm sido testadas estratégias terapêuticas a fim de modular a geração ou a função excessiva de mediadores na sepse. OBJETIVO: O objetivo deste estudo foi investigar o efeito terapêutico da N-acetilcisteína (NAC) e sua associação com a frutose-1,6-bisfosfato (FBP) sobre a proliferação de linfócitos T e a geração de interleucina-1β (IL-1β) e proteína quimiotática de monócitos 1 (MCP-1) em cultura celular. MATERIAL E MÉTODOS: Foram isoladas células mononucleares de sangue periférico de indivíduos saudáveis. Os linfócitos T foram estimulados por 96 horas com fitohemaglutinina e submetidos a diferentes concentrações de NAC ou NAC associada à FBP (1,25 mM). RESULTADOS: O tratamento com NAC (10 e 15 mM) ou NAC (15 mM) associado à FBP reduziu a proliferação celular. Os níveis de IL-1β aumentaram com a presença de NAC (15 mM) e NAC + FBP. A concentração de MCP-1 mostrou-se reduzida apenas no grupo tratado com NAC associada à FBP. CONCLUSÃO: Os resultados sugerem que tanto a NAC quanto a NAC associada à FBP são capazes de inibir a proliferação celular, atuando como potentes agentes imunomoduladores, sugerindo seu uso em doenças inflamatórias.

Effect of N-acetylcysteine and fructose-1,6-bisphosphate in the treatment of experimental sepsis.

Sepsis is a syndrome caused by uncontrolled systemic inflammatory response of the individual, which represents a serious epidemiological problem worldwide. The aim of this study was to investigate the effect of N-acetylcysteine (NAC) and fructose-1,6-bisphosphate (FBP) in the treatment of experimental sepsis. We used rats that were divided into five experimental groups: normal control (not induced), septic control (induced using a capsule with non sterile fecal content and Escherichia coli), treated with FBP (500 mg/kg i.p.), treated with NAC (150 mg/kg i.p.), and treated with the combination of FBP with NAC. In the group treated with NAC, 16.68% of the mice survived, the FBP reduced the mortality of mice during the acute stage of the disease and increased the animals' survival time in 33.34%, and the combination of drugs had no effect. Our results show that NAC prevented the mortality of animals after septic induction. These data confirm the validity of the use of NAC in the treatment of sepsis. Our data also show that the synergistic action with FBP does not improve the picture.

Fructose-1,6-bisphosphate and MK-801 by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 min in dogs. An exploratory study.

In our exsanguination cardiac arrest (CA) outcome model in dogs we are systematically exploring suspended animation (SA), i.e. preservation of brain and heart immediately after the onset of CA to enable transport and resuscitative surgery during CA, followed by delayed resuscitation. We have shown in dogs that inducing moderate cerebral hypothermia with an aortic arch flush of 500 ml normal saline solution at 4 degrees C, at start of CA 20 min no-flow, leads to normal functional outcome. We hypothesized that, using the same model, but with the saline flush at 24 degrees C inducing minimal cerebral hypothermia (which would be more readily available in the field), adding either fructose-1,6-bisphosphate (FBP, a more efficient energy substrate) or MK-801 (an N-methyl-D-aspartate (NMDA) receptor blocker) would also achieve normal functional outcome. Dogs (range 19-30 kg) were exsanguinated over 5 min to CA of 20 min no-flow, and resuscitated by closed-chest cardiopulmonary bypass (CPB). They received assisted circulation to 2 h, mild systemic hypothermia (34 degrees C) post-CA to 12 h, controlled ventilation to 20 h, and intensive care to 72 h. At CA 2 min, the dogs received an aortic arch flush of 500 ml saline at 24 degrees C by a balloon-tipped catheter, inserted through the femoral artery (control group, n=6). In the FBP group (n=5), FBP (total 1440 or 4090 mg/kg) was given by flush and with reperfusion. In the MK-801 group (n=5), MK-801 (2, 4, or 8 mg/kg) was given by flush and with reperfusion. Outcome was assessed in terms of overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, brain death or death), neurologic deficit scores (NDS 0-10%, normal; 100%, brain death), and brain histologic damage scores (HDS, total HDS 0, no damage; >100, extensive damage; 1064, maximal damage). In the control group, one dog achieved OPC 2, one OPC 3, and four OPC 4; in the FBP group, two dogs achieved OPC 3, and three OPC 4; in the MK-801 group, two dogs achieved OPC 3, and three OPC 4 (P=1.0). Median NDS were 62% (range 8-67) in the control group; 55% (range 34-66) in the FBP group; and 50% (range 26-59) in the MK-801 group (P=0.2). Median total HDS were 130 (range 56-140) in the control group; 96 (range 64-104) in the FBP group; and 80 (range 34-122) in the MK-801 group (P=0.2). There was no difference in regional HDS between groups. We conclude that neither FBP nor MK-801 by aortic arch flush at the start of CA, plus an additional i.v. infusion of the same drug during reperfusion, can provide cerebral preservation during CA 20 min no-flow. Other drugs and drug-combinations should be tested with this model in search for a breakthrough effect.

New advances in the treatment of sickle cell disease: focus on perioperative significance.

Sickle cell diseases comprise a group of inherited disorders that alter hemoglobin, ultimately causing hemolytic anemia and reoccurring instances of vascular occlusion that produce acute and chronic pain. Many patients with sickle cell disease require surgery for conditions associated with their disease. Painful vaso-occlusive episodes, which can be debilitating and require long hospital stays, are often precipitated by the stress of surgery. Poorly controlled postoperative pain also can worsen an impending painful crisis. Traditional therapy for patients with sickle cell disease undergoing surgery has included preoperative transfusion and postoperative opioid therapy. Recent studies have demonstrated that aggressive preoperative transfusion therapy is not beneficial over a more conservative approach. Postoperative pain control trends include nonsteroidal anti-inflammatory drugs such as ketorolac and opioid agonist-antagonist agents such as nalbuphine, as well as epidural analgesia to minimize respiratory depression. New preventive therapy for vaso-occlusive crisis includes hydroxyurea, a chemotherapeutic agent that stimulates the production of fetal hemoglobin. Inhaled nitric oxide is being used in clinical trials with success in slowing the sickling process and unsickling cells. Phase III clinical trials are in progress for 2 drugs that decrease sickling: poloxamer 188 and fructose 1-6 diphosphate. These new therapies should help improve the anesthetic course of the patient with sickle cell disease, reduce postoperative complications, and shorten hospital stays.

Efeito da frutose-1, 6-bifosfato na preservação de rins de ratos / Effects of Fructose-1, 6-diphosphate on kidney preservation of rats

A perfusão para preservaçao de rins para transplantes tem por finalidade a manutenção da viabilidade do órgão, lavá-lo internamente para remover o sangue e de manter a atividade celular até a revascularização. A frutose-1, 6- bisfosfato apresenta efeito de proteção celular em situações diversas, tais como isquemia e toxicidade de drogas...

Efeito da frutose-1, 6-bifosfato na preservaçäo de rins de ratos / Effects of Fructose-1, 6-diphosphate on kidney preservation of rats

A perfusão para preservaçao de rins para transplantes tem por finalidade a manutenção da viabilidade do órgão, lavá-lo internamente para remover o sangue e de manter a atividade celular até a revascularização. A frutose-1, 6- bisfosfato apresenta efeito de proteção celular em situações diversas, tais como isquemia e toxicidade de drogas...

[Pharmacological intervention in experimental multiple organ failure in rats].

This paper presents a primary study of the treatment of experimental multiple system organ failure (MSOF) in rats. The rats were pretreated with xanthine oxidase inhibitor allopurinol, the energy metabolism regulator fructose-1,6-diphosphate (FDP) and purified Chinese herbal medicine polydatin. The incidence of MSOF decreased from 71.4% in the untreated group to 35.7%, 47.1% and 16.7% in treated groups, respectively, while the mean survival time was prolonged to 38.5h, 30.2h and 41.7h in treated groups, respectively, as compared with 26.4h in the untreated group. In addition to the known antioxidant effect of the allopurinol, this study also suggests that FDP and polydatin enhance the capacity of antioxidtion.

Effects of FDP and Danshen on renal cortical Na-K-ATPase activity in rats after treatment with renal ischemia and gentamicin.

The main purpose of our study is to investigate the possible protective effects of Fructose 1-6 diphosphate (FDP) and Danshen (Salvia Miltiozzhiza Bunze) on renal cortical Na-K-ATPase activity after renal ischemia and gentamicin nephrotoxicity. An 18.6% reduction in renal cortical Na-K-ATPase activity was shown after 30 min of renal pedicle clamping and 60 min of reflow, and a 32.5% reduction after 90 min of single injection of 100 mg/kg gentamicin. Light and electronic microscopy revealed no significant morphologic changes in both groups in the experiment. 4g/kg FDP and 18g/kg Danshen were infused 60 min after reflow in the ischemic group, 90 min after injection of gentamicin in the gentamicin-treated group and 90 min in the sham-operated group separately. The enzyme activity in the FDP-treated groups was found to be higher than that in the control kidneys while in the Danshen-treated groups no significant difference could be found. Our study showed that FDP and Danshen could prevent the decline of renal cortical Na-K-ATPase activity induced by ischemia and gentamicin. FDP could increase this enzyme activity while Danshen showed no such direct effect.