Fructose-derived advanced glycation end-products drive lipogenesis and skeletal muscle reprogramming via SREBP-1c dysregulation in mice.

Advanced Glycation End-Products (AGEs) have been recently related to the onset of metabolic diseases and related complications. Moreover, recent findings indicate that AGEs can endogenously be formed by high dietary sugars, in particular by fructose which is widely used as added sweetener in foods and drinks. The aim of the present study was to investigate the impact of a high-fructose diet and the causal role of fructose-derived AGEs in mice skeletal muscle morphology and metabolism. C57Bl/6J mice were fed a standard diet (SD) or a 60% fructose diet (HFRT) for 12 weeks. Two subgroups of SD and HFRT mice received the anti-glycative compound pyridoxamine (150 mg/kg/day) in the drinking water. At the end of protocol high levels of AGEs were detected in both plasma and gastrocnemius muscle of HFRT mice associated to impaired expression of AGE-detoxifying AGE-receptor 1. In gastrocnemius, AGEs upregulated the lipogenesis by multiple interference on SREBP-1c through downregulation of the SREBP-inhibiting enzyme SIRT-1 and increased glycation of the SREBP-activating protein SCAP. The AGEs-induced SREBP-1c activation affected the expression of myogenic regulatory factors leading to alterations in fiber type composition, associated with reduced mitochondrial efficiency and muscular strength. Interestingly, pyridoxamine inhibited AGEs generation, thus counteracting all the fructose-induced alterations. The unsuspected involvement of diet-derived AGEs in muscle metabolic derangements and proteins reprogramming opens new perspectives in pathogenic mechanisms of metabolic diseases.

Primary PCI for the treatment of ectatic infarct-related coronary artery.

AIM: There is lack of information on the outcome of patients treated with primary angioplasty for lesions located in an ectatic coronary artery segment in the setting of acute myocardial infarction. The aim of this study was to analyse the 2-year follow-up of this specific patient population. METHODS: By means of a systematic review of the databases and cine-films of 5912 primary angioplasties performed in eight Italian cardiac centers we identified 101 patients with infarct-related coronary artery ectasia. Ectasia was defined as a dilatation exceeding the 1.5-fold of normal adjacent segment and was classified according to its severity. The primary end point was the composite rate of cardiac death, recurrence of acute myocardial infarction and a new revascularisation at 2-year. RESULTS: The procedure was successful in 70.3% of cases, unsuccessful or complicated in 29.7%. The primary endpoint was met in 6.9% of cases during hospitalization (95% CI: 2.0-11.8), in 17.8% (95% CI: 10.3-25.3) at 1 year, and in 38.5% (95% CI: 29.0-48.0) at 2 years. Nine patients had a stent thrombosis: 3 acute and 6 sub-acute. A statistically significant correlation between the dimensions of the stent and stent thrombosis was observed (P=0.005). CONCLUSION: In subjects undergoing primary angioplasty for acute myocardial infarction the rate of patients treated on lesions located in an ectatic coronary artery segment is very small (1.7%). The procedural success was low, whereas the rate of events at follow-up was quit high reflecting the complexity of this disease.

Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics.

BACKGROUND: Survival rates among childhood cancer survivors (CCS) have enormously increased in the last 40 years. However, this improvement has been achieved at the expense of serious late effects that frequently involve the endocrine system. AIM: To evaluate the cumulative incidence of endocrine diseases in a cohort of long-term CCS. MATERIALS AND METHODS: We analyzed the clinical data of 310 adults, followed for a median time of 16.0 years after the first cancer diagnosis. The monitoring protocols applied to each patient were personalized on the basis of cancer diagnosis and previous treatments, according to the Children's Oncology Group guidelines. RESULTS: The cumulative incidence of endocrine late effects steadily increased over time. At the last follow-up visit available, 48.46% of females and 62.78% of males were affected by at least one endocrine disease. The most common disorders were gonadal dysfunction, primary hypothyroidism, and GH deficiency (GHD). The main risk factors for endocrine disease were male sex (hazard ratio (HR)=1.45, 95% confidence interval (95% CI) 1.05-1.99), radiotherapy (HR=1.91, 95% CI 1.28-2.84), hematopoietic stem cells transplantation (HR=3.11, 95% CI 2.23-4.34), and older age at cancer diagnosis (HR=1.89, 95% CI 1.25-2.85). Male sex was associated with a higher risk of gonadal disorders, whereas radiotherapy specifically increased the risk of GHD and thyroid dysfunction. CONCLUSIONS: Endocrine disorders among CCS have a high prevalence and increase over time. Thus, endocrinologists need to cope with an increasing demand for health care in a field that is still little developed and that, in perspective, could also be extended to some selected types of adult cancer survivors.

The pan-DAC inhibitor LBH589 is a multi-functional agent in breast cancer cells: cytotoxic drug and inducer of sodium-iodide symporter (NIS).

New drugs with anti-tumor activity, also able to modify the expression of selected molecules, are under evaluation in breast cancer which is becoming resistant to conventional treatment, or in metastatic disease. The sodium-iodide symporter (NIS), which mediates iodide uptake into thyroid cells, and is the molecular basis of radioiodine imaging and therapy in thyroid cancer, is also expressed in a large portion of breast tumors. Since NIS expression in breast cancer is not sufficient for a significant iodide uptake, drugs able to induce its expression and correct function are under evaluation. In the present study, we report for the first time that the pan-deacetylase (DAC) inhibitor LBH589 (panobinostat) significantly induced NIS, both as mRNA and as protein, through the increase of NIS promoter activity, with the final consequence of obtaining a significant up-take of iodide in MCF7, T47D, and MDA-MB231 breast cancer cells. Moreover, we observed that LBH589 causes a significant reduction in cell viability of estrogen-sensitive and -insensitive breast cancer cells within nanomolar range. The anti-tumor effect of LBH589 is sustained by apoptosis induction and cell cycle arrest in G(2)/M. In conclusion, our data suggest that LBH589 might be a powerful tool in the management of breast cancer due to its multiple effects and support a potential application of LBH589 in the diagnosis and treatment of this disease.

Sex Hormone-Binding Globulin (SHBG), estradiol and breast cancer.

The human serum Sex Hormone-Binding Globulin (SHBG) plays an important role in breast cancer pathophysiology and risk definition, since it regulates the bioavailable fraction of circulating estradiol. We here summarize data reported over the years concerning the involvement of SHBG and SHBG polymorphisms in the definition of breast cancer risk. We also report what is known about the direct action of SHBG in breast cancer cells, illustrating its interaction with these cells and the subsequent initiation of a specific intracellular pathway leading to cross-talk with the estradiol-activated pathway and, finally, to the inhibition of several effects of estradiol in breast cancer cells. In conclusion, as a result of its unique property of regulating the estrogen free fraction and cross-talking with the estradiol pathways, by inhibiting estradiol-induced breast cancer cell growth and proliferation, SHBG is associated with a reduced risk of developing the neoplasm after estrogen exposure.

Valproic acid restores ER alpha and antiestrogen sensitivity to ER alpha-negative breast cancer cells.

Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor alpha (ER alpha) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ER alpha expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ER alpha mRNA and protein, while did not modify ER beta. In VPA-treated cells, we also observed: (1) a correct transcriptional response to estradiol after transfection with the luciferase gene under the control of an estrogen-responsive minimal promoter (ERE-TKluc); (2) increased expression of the ER-related transcription factor FoxA1; (3) estradiol-induced up-regulation of several estrogen-regulated genes (e.g. pS2, progesterone receptor); (4) inhibitory effect of tamoxifen on cell growth. In conclusion, the HDI VPA, inducing ER alpha and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive "phenotype", restoring their sensitivity to antiestrogen therapy.

Cardiac impairment in rabbits fed a high-fat diet is counteracted by dehydroepiandrosterone supplementation.

AIMS: The biochemical and structural cardiac oxidative-dependent damage induced by high-fat (HF) diet was examined in a rabbit model, together with the role of dehydroepiandrosterone (DHEA) in contrasting tissue damage. MAIN METHODS: New Zealand white rabbits fed a HF diet supplemented or not with DHEA (0.02%) were utilized for 12 weeks. Oxidative stress, inflammatory and necrosis parameters, fatty deposition, heavy-chain myosin isoforms (MHC) expression and papillary muscle functionality were examined in the left ventricle of rabbits. KEY FINDINGS: Rabbits fed a HF diet that showed hyperglycemia, insulin resistance and dyslipidemia together with increase of oxidative stress and of advanced end-glycation product levels have been observed. Concerning pro-inflammatory insults, there was increased p65-NFkB activation and increased tumor necrosis factor-alpha and C-reactive protein expressions. Cellular damage induced by the HF diet was detected through the switch of expression of MHC isoforms, indicating impairment of cardiac contractility, confirmed by altered of basal parameters of papillary muscle functionality. Rabbits fed the HF diet supplemented with DHEA showed a partial reduction of oxidative stress and the inflammatory state. Cardiac necrosis, the shift of MHC isoforms, and cardiac functionality, were also partially counteracted. SIGNIFICANCE: Rabbits fed with a HF diet showed a beneficial effect when low-dose DHEA was added to the diet. The steroid, without affecting high plasma glucose level or insulin resistance, restored oxidative balance, lowered lipid levels and inflammation insults, preventing cellular and functional alterations of cardiac tissue and thus delaying the onset of cardiac damage.

Sex hormone-binding globulin selectively modulates estradiol-regulated genes in MCF-7 cells.

Human sex hormone-binding globulin inhibits the effects of estradiol on proliferation and apoptosis of breast cancer cells. We report here the effect of sex hormone-binding globulin on estradiol regulation of gene expression in MCF-7 breast cancer cells using a selected set of genes. Estradiol upregulates genes that are positive regulators of proliferation (e.g., bcl-2, c-fos, c-myc, cyclin D) or/and related to more aggressive form of breast cancer (e.g. BRCA-1, EGF-R) and downregulates two genes (c-jun and ERalpha). Sex hormone-binding globulin modulates only a selected group of estradiol-controlled genes (inhibiting upregulation of bcl-2, c-myc, EGF-R, PR, and downregulation of ERalpha), starting 48 hours after treatment. Our study demonstrates that in breast cancer cells, sex hormone-binding globulin is effective on few selected genes which are involved in cell growth and apoptosis or related to cell estrogen-dependence and that the protein regulation of estradiol effect is selected and specific. Sex hormone-binding globulin action in estrogen breast cancer cells is strongly associated to cell growth and estrogen-sensitivity.

High energy shock waves activate 5'-aminolevulinic Acid and increase permeability to Paclitaxel: antitumor effects of a new combined treatment on anaplastic thyroid cancer cells.

OBJECTIVE: Multimodal treatments do not meaningfully improve survival of anaplastic thyroid cancer. Consequently, new effective therapeutic modalities are needed. The use of paclitaxel is under clinical investigation; it shows about a 50% response rate, but it is not able to alter the fatal outcome for patients with anaplastic carcinoma. High energy shock waves (HESW) have been shown to cause a transient increase in the permeability of cell membranes thus allowing higher intracellular drug concentrations. 5-Aminolevulinic acid (ALA) is used in the photodynamic therapy (PDT) of cancer, and HESW are under evaluation for their use as an activator in ALA-PDT. DESIGN: We investigated the effect of HESW produced by a piezoelectric generator on the sensitivity to paclitaxel and ALA treatments of two different anaplastic thyroid cancer cell lines (ARO and CAL-62). Cells, treated sequentially with ALA and paclitaxel were exposed to HESW; thereafter, cell viability and apoptosis induction were evaluated. MAIN OUTCOME: Combined exposure to ALA, paclitaxel, and shock waves resulted in a significant enhancement of cytotoxicity and induction of apoptosis in thyroid cancer cells with respect to cells treated with paclitaxel alone. CONCLUSIONS: These preliminary data suggest the possibility of using HESW and ALA in combination with paclitaxel as a promising new therapy in the treatment of anaplastic thyroid cancer.

Drug eluting stents in acute myocardial infarction.

Routine stent-implantation in primary coronary intervention (PCI) for acute myocardial infarction (AMI) has been shown to have a better clinical outcome than balloon angioplasty mainly because of reduction in restenosis rate and reocclusion. Drug eluting stents (DES) have recently been proven to further reduce restenosis and revascularization rate in comparison to bare metal stent (BMS) in elective procedures. Delayed endothelialization of these stents raises concern about a possible increase of thrombotic complications in the setting of AMI. Randomized studies with DES in the treatment of elective patients have shown at 9-12 months follow-up a thrombosis rate of 0-2% comparable to the one of BMS. Sirolimus eluting stents (SES) in AMI have been used in small series of consecutive pts not randomized or in registries with very high successful rate and a stent thrombosis varying between 0 and 4.7%. Paclitaxel eluting stent (PES) have also shown in small series a good immediate performance with a thrombosis rate between 0 and 4.8%. Predictors of acute and subacute stent thrombosis are the same than for BMS: residual dissection, long or overlapping stents, biforcation lesions and discontinuation of antiplatelets treatment. Providing effective mechanical reperfusion with similar results to the current therapeutic standard and decreasing the incidence of late complications, DES appear as an attractive approach for patients admitted with AMI.

Oxidative and nitrosative stress in brain mitochondria of diabetic rats.

Diabetic encephalopathy, characterized by impaired cognitive functions and neurochemical and structural abnormalities, may involve direct neuronal damage caused by intracellular glucose. The study assesses the direct effect of chronic hyperglycemia on the function of brain mitochondria, the major site of reactive species production, in diabetic streptozotocin (STZ) rats. Oxidative stress plays a central role in diabetic tissue damage. Alongside enhanced reactive oxygen species (ROS) levels, both nitric oxide (NO) levels and mitochondrial nitric oxide synthase expression were found to be increased in mitochondria, whereas glutathione (GSH) peroxidase activity and manganese superoxide dismutase protein content were reduced. GSH was reduced and GSH disulfide (GSSG) was increased in STZ rats. Oxidative and nitrosative stress, by reducing the activity of complexes III, IV and V of the respiratory chain and decreasing ATP levels, might contribute to mitochondrial dysfunction. In summary, this study offers fresh evidence that, besides the vascular-dependent mechanisms of brain dysfunction, oxidative and nitrosative stress, by damaging brain mitochondria, may cause direct injury of neuronal cells.

Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in breast cancer cells.

Sex hormone-binding globulin, the plasma carrier for sex steroids, inhibits the estradiol-induced proliferation of breast cancer cells. Estradiol induces cell proliferation triggering multiple mechanisms. Besides regulating growth factors, it activates Erk-1/-2, thus inhibiting apoptosis. In the present study, we investigated the effect of SHBG on estradiol-mediated anti-apoptotic effect in MCF-7 breast cancer cells. As expected, estradiol reduced the number of cells undergoing apoptosis. Although no modification of estradiol action was observed in cells treated contemporarily with estradiol and SHBG, pre-incubation with SHBG before estradiol treatment contrasted the anti-apoptotic effect completely. A mutant form of SHBG, lacking the O-linked oligosaccharide in Thr(7), displayed no such effect. Moreover, SHBG prevented the estradiol-induced phosphorylation of Erk-1/-2, whereas it had no effect on estradiol-induced transcription. Taken together, our observations suggest that the interaction of SHBG with MCF-7 cell membranes causes inhibition of the anti-apoptotic effect of estradiol which might account for SHBG's inhibitory effect on breast cancer cell growth.

Ectopic secretion of LH by an endocrine pancreatic tumor.

Ectopic production of biologically active glycoprotein hormones other than hCG has been reported in exceptional cases. A 61-yr-old man came to our Unit complaining of weakness, fatigue and reduced libido with erectile dysfunction. There was also a history of polycythemia, known for about 10 yr and never further investigated. The physical examination showed acne and redness of facial skin and upper chest; no other significant abnormalities were detected. Serum levels of LH were very high, whereas alpha-subunit and hCG were only slightly increased. Testosterone and 17beta-estradiol levels were increased too. Abdominal computed tomography (CT) scan revealed a large hypervascularized mass within the pancreatic tail, which was surgically removed by distal splenopancreatectomy. Diffuse immunoreactivity for LH was detected in more than 70% of the tumor cells. The alpha-subunit was also positive, while chorionic gonadotropin had only a focal reactivity. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern Blot analysis confirmed the synthesis of LH by the tumor. Four weeks after surgery, serum levels of LH, alpha-subunit, testosterone, hCG and 17beta-estradiol were all undetectable. The redness of facial skin and upper chest had disappeared, but libido was still reduced. At a further control, 3 months after surgery, serum levels of LH, FSH, hCG, alpha-subunit and 17beta-estradiol were all within the normal range, as well as hemoglobin concentration and the red blood cells count. Testosterone was slightly below normal, but the patient reported an increase of libido. This is an unusual case of ectopic secretion of LH from an endocrine tumor of the pancreas.

Procedural and long-term results of sirolimus-eluting stent in patients at high risk for restenosis.

AIM: In-stent restenosis still affects 10-50% of long-term outcome after percutaneous coronary intervention (PCI). Large clinical trials have shown that sirolimus-eluting stents (SES) have reduced restenosis rate to 0-9% in lesions at low-moderate risk. The aim of this study was to evaluate long-term clinical and angiographic outcome of SES in a real world population, at very high risk of restenosis. METHODS: Ninety lesions at high risk of restenosis (lesion length >20 mm, target vessel diameter <2.5 mm, in-stent diffuse restenosis, total occlusions and complex lesions on bypass grafts and bifurcations) were treated in 75 patients. A follow-up was scheduled at 6 months. RESULTS: Restenosis rate was 16.6% with a focal pattern of presentation in most cases. Subacute in-stent thrombosis occurred in 2.2%. Resteno-sis occurred mainly in small vessels, diabetic patients and in vessels previously treated with brachytherapy. CONCLUSION: The treatment of lesions at high risk of restenosis with SES is safe with a low restenosis rate at follow-up. An aggressive and prolonged antiplatelet regimen is mandatory because of high subacute in-stent thrombosis rates.

Oxidative stress and eicosanoids in the kidneys of hyperglycemic rats treated with dehydroepiandrosterone.

Oxidative stress plays a crucial role in the pathogenesis of chronic diabetic complications. Normoglycemic and streptozotocin-diabetic rats were treated with dehydroepiandrosterone (DHEA) (4 mg/d per rat) for 3 weeks. At the end of treatment, hydroxynonenal, hydroperoxyeicosatetraenoic acids and antioxidant levels, as well as Na/K-ATPase activity and membrane fatty acids composition were evaluated in kidney homogenates. Chronic hyperglycemia caused a marked increase of both hydroxynonenal and lipoxygenase pathway products and a drop in both GSH levels and membrane Na/K-ATPase activity. DHEA treatment restored the antioxidant levels to close to the control value and considerably reduced hydroxynonenal and hydroperoxyeicosatetraenoic acid levels. Moreover, DHEA counteracted the detrimental effect of hyperglycemia on membrane function: the drop of Na/K-ATPase activity in diabetic animals was significantly inhibited by DHEA treatment. These results show that DHEA reduces oxidative stress and the consequent increase of lipoxygenase pathway products induced by experimental diabetes in rat kidney; they also suggest that, by reducing the inflammatory response to oxidative stress, DHEA treatment might delay the progression of diabetic kidney disease.

Dehydroepiandrosterone prevents oxidative injury induced by transient ischemia/reperfusion in the brain of diabetic rats.

Both chronic hyperglycemia and ischemia/reperfusion (IR) cause an imbalance in the oxidative state of tissues. Normoglycemic and streptozotocin (STZ)-diabetic rats were subjected to bilateral carotid artery occlusion for 30 min followed by reperfusion for 60 min. Rats had either been treated with dehydroepiandrosterone (DHEA) for 7, 14, or 21 days (2 or 4 mg/day per rat) or left untreated. Oxidative state, antioxidant balance, and membrane integrity were evaluated in isolated synaptosomes. IR increased the levels of reactive species and worsened the synaptic function, affecting membrane Na/K-ATPase activity and lactate dehydrogenase release in all rats. The oxidative imbalance was much severer when transient IR was induced in STZ-diabetic rats. DHEA treatment restored H2O2, hydroxyl radical, and reactive oxygen species to close to control levels in normoglycemic rats and significantly reduced the level of all reactive species in STZ-diabetic rats. Moreover, DHEA treatment counteracted the detrimental effect of IR on membrane integrity and function: the increase of lactate dehydrogenase release and the drop in Na/K-ATPase activity were significantly prevented in both normoglycemic and STZ-diabetic rats. The results confirm that DHEA, an adrenal steroid that is synthesized de novo by brain neurons and astrocytes, possesses a multitargeted antioxidant effect. They also show that DHEA treatment is effective in preventing both derangement of the oxidative state and neuronal damage induced by IR in experimental diabetes.

Dehydroepiandrosterone prevents lipid peroxidation and cell growth inhibition induced by high glucose concentration in cultured rat mesangial cells.

The oxidative stress induced by high glucose concentration contributes to tissue damage associated with diabetes, including renal injury. Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal gland, has been shown to possess a multi-targeted antioxidant activity which is also effective against lipid peroxidation induced by high glucose. In this study we evaluated the effect of DHEA on the growth impairment which high glucose concentration induces in cultured rat mesangial cells. Primary cultures of rat mesangial cells were grown for 10 days in media containing either normal (i.e. 5.6 mmol/l) or high (i.e. 30 mmol/l) concentrations of glucose, without or with DHEA at different concentrations. The impairment of cell growth induced by high glucose was reversed by 100 nmol/l and 500 nmol/l DHEA, which had no effect on mesangial cells cultured in media containing glucose at the normal physiological concentration (5.6 mmol/l). In high-glucose cultured mesangial cells, DHEA also attenuated the lipid peroxidation, as measured by thiobarbituric acid reactive substances (TBARS) generation and 4-hydroxynonenal (HNE) concentration, and preserved the cellular content of reduced glutathione as well as the membrane Na+/K+ ATPase activity. The data further support the protective effect of DHEA against oxidative damage induced by high glucose concentrations, and bring into focus its possible effectiveness in preventing chronic complications of diabetes.

NT2 neurons, a classical model for Alzheimer's disease, are highly susceptible to oxidative stress.

We have tested undifferentiated NT2 cells as well as differentiated NT2 neurons (NT2N) for vulnerability to oxidative stress, lipid composition and antioxidant pattern. NT2N, but not NT2 cells, are highly susceptible to oxidative stress elicited by different classic pro-oxidant stimuli. In particular, NT2N cells undergo a high level of oxidative decomposition of omega-3 and omega-6 polyunsaturated fatty acids (PUFA) of membrane phospholipids, as evaluated by monitoring generation of thiobarbituric reactive substances, 4-hydroxynonenal (HNE) and chromolipid fluorescent adducts. NT2N cells exhibit low levels of natural antioxidants such as glutathione (GSH) and alpha-tocopherol and of antioxidant enzymatic activities such as Se-dependent GSH peroxidase and catalase. Accordingly, a direct correlation between lipid peroxidation and irreversible cell damage is suggested by prevention of NT2N cell death by alpha-tocopherol.

Oxidative derangement in rat synaptosomes induced by hyperglycaemia: restorative effect of dehydroepiandrosterone treatment.

Central nervous system damage in diabetes is caused by both cerebral atherosclerosis and the detrimental effect of chronic hyperglycaemia on nervous tissue. Hyperglycaemia is the primer of a series of cascade reactions causing overproduction of free radicals. There is increasing evidence that these reactive molecules contribute to neuronal tissue damage. Dehydroepiandrosterone (DHEA) has been reported to possess antioxidant properties. This study evaluates the oxidative status in the synaptosomal fraction isolated from the brain of streptozotocin-treated rats and the antioxidant effect of DHEA treatment on diabetic rats. Hydroxyl radical generation, hydrogen peroxide content, and the level of the reactive oxygen species was increased (P<0.05) in synaptosomes isolated from streptozotocin-treated rats. The derangement of the oxidative status was confirmed by a low level of reduced glutathione and alpha-tocopherol. DHEA treatment (4 mg per day for 3 weeks, per os) protected the synaptosomes against oxidative damage: synaptosomes from diabetic DHEA-treated rats showed a significant decrease in reactive species (P<0.05) and in the formation of end products of lipid peroxidation, evaluated in terms of fluorescent chromolipid (P<0.01). Moreover, DHEA treatment restored the unsaturated fatty acid content of the membrane and the reduced glutathione and alpha-tocopherol levels to normal levels and restored membrane NaK-ATPase activity close to control levels. The results demonstrate that DHEA supplementation greatly reduces oxidative damage in synaptosomes isolated from diabetic rats and suggest that this neurosteroid may participate in protecting the integrity of synaptic membranes against hyperglycaemia-induced damage.