Role of the inhibition of oxidative stress and inflammatory mediators in the neuroprotective effects of hydroxytyrosol in rat brain slices subjected to hypoxia reoxygenation.

The aim of this study was to analyze the mechanism of the neuroprotective effect of hydroxytyrosol (HT) in an experimental model of hypoxia-reoxygenation in rat brain slices. After reoxygenation the increase in lactate dehydrogenase efflux was inhibited by HT in a concentration-dependent manner and dose-dependent inhibition after oral administration to rats for 7 days (1, 5 and 10 mg/kg per day). Maximum inhibition was 57.4% in vitro and 38.7% ex vivo. Hydroxytyrosol reduced oxidative stress parameters: it inhibited lipid peroxidation and increased enzymatic activities related with the glutathione system both in vitro and after oral administration to rats. The increase in prostaglandin E2 and interleukin 1ß after reoxygenation were inhibited after incubation of brain slices with HT and after oral administration. The accumulation of nitric oxide in brain slices was reduced in a concentration-dependent manner. In conclusion, HT exerts a neuroprotective effect in a model of hypoxia-reoxygenation in rat brain slices, both in vitro and after 7 days of oral administration to rats. HT exerts an antioxidant activity and lowered some inflammatory markers in this model.

Clinical outcomes of minimally invasive versus open approach for one-level transforaminal lumbar interbody fusion at the 3- to 4-year follow-up.

PURPOSE: Supporters of minimally invasive approaches for transforaminal lumbar interbody fusion (TLIF) have reported short-term advantages associated with a reduced soft tissue trauma. Nevertheless, mid- and long-term outcomes and specifically those involving physical activities have not been adequately studied. The aim of this study was to compare the clinical outcomes of mini-open versus classic open surgery for one-level TLIF, with an individualized evaluation of the variables used for the clinical assessment. METHODS: A prospective cohort study was conducted of 41 individuals with degenerative disc disease who underwent a one-level TLIF from January 2007 to June 2008. Patients were randomized into two groups depending on the type of surgery performed: classic open (CL-TLIF) group and mini-open approach (MO-TLIF) group. The visual analog scale (VAS), North American Spine Society (NASS) Low Back Pain Outcome instrument, Oswestry Disability Index (ODI) and the Short Form 36 Health Survey (SF-36) were used for clinical assessment in a minimum 3-year follow-up (36-54 months). RESULTS: Patients of the MO-TLIF group presented lower rates of lumbar (p = 0.194) and sciatic pain (p = 0.427) and performed better in daily life activities, especially in those requiring mild efforts: lifting slight weights (p = 0.081), standing (p = 0.097), carrying groceries (p = 0.033), walking (p = 0.069) and dressing (p = 0.074). Nevertheless, the global scores of the clinical questionnaires showed no statistical differences between the CL-TLIF and the MO-TLIF groups. CONCLUSIONS: Despite an improved functional status of MO-TLIF patients in the short term, the clinical outcomes of mini-open TLIF at the 3- to 4-year follow-up showed no clinically relevant differences to those obtained with open TLIF.

Hydroxytyrosyl alkyl ether derivatives inhibit platelet activation after oral administration to rats.

The low lipophilicity of hydroxytyrosol (HT) has motivated efforts to synthesize homologous series with better lipid solubility, such as the ethers, which are more lipophilic than HT. Because HT inhibits platelet aggregation, the aim of the study was to assess the possible anti-platelet effect of five HT ether derivatives (ethyl, butyl, hexyl, octyl and dodecyl) after oral administration to rats. Whole blood collagen-induced platelet aggregation and calcium-induced thromboxane B2 (TxB2), aortic 6-keto-prostaglandin F1α (6-keto-PGF1α) and nitrites+nitrates, plasma concentration of lipid peroxides (TBARS) and red blood cell content of reduced glutathione (GSH) were measured. The administration of 20 mg/kg/day inhibited platelet aggregation, TxB2 and TBARS in a non-linear manner related to the length of the carbon chain, with a cut-off effect in the hexyl derivative. Aortic nitrite and red blood cell GSH production were also increased. The aortic production of 6-keto-PGF1α was unaltered except in the group treated with the dodecyl derivative. The administration of 50 mg/kg/day showed a similar pharmacodynamic profile but without the non-linear effect. In conclusion, HT ethers, especially the hexyl derivative, are a potential alternative to hydroxytyrosol, and their effect merits additional research to determine their role in the prophylaxis of vascular disease.

Cytoprotective effect of hydroxytyrosyl alkyl ether derivatives after oral administration to rats in a model of glucose-oxygen deprivation in brain slices.

This study was designed to determine whether the oral administration of hydroxytyrosol (HT) alkyl ether derivatives has a neuroprotective effect in rats. The animals were treated for 7 days with HT or ethyl, butyl, hexyl, octyl, and dodecyl HT ether. A method of in vitro hypoxia-reoxygenation in brain slices was used. Hexyl, octyl, and dodecyl HT derivatives reduced brain cell death (LDH efflux). Lipid peroxidation and nitrite concentrations were inhibited most by hexyl, octyl, and dodecyl derivatives. Concentrations of 3-nitrotyrosine were reduced by HT butyl, hexyl, octyl, and dodecyl ether derivatives. Interleukin-1ß was significantly reduced in brain slices from rats treated with all HT ether derivatives. LDH efflux showed a linear correlation with brain concentrations of lipid peroxides, nitrites plus nitrates, and interleukin 1ß. The reduction in oxidative and nitrosative stress and decreased production of pro-inflammatory interleukins may be the basis for the observed neuroprotective effects.

Cytoprotective effect of nonsteroidal antiinflammatory drugs in rat brain slices subjected to reoxygenation after oxygen-glucose deprivation.

The aim of this study was to assess the possible neuroprotective effect of the main nonsteroidal antiinflammatory drugs (NSAIDs) in an experimental model of hypoxia-reoxygenation in rat brain slices. After reoxygenation the increase in lactate dehydrogenase (LDH) efflux was inhibited by nimesulide, celecoxib and meloxicam with an IC(50) in the 10(-6)M range, by flurbiprofen, ibuprofen and diclofenac in the 10(-5)M range, and by salicylic acid, indomethacin, acetylsalicylic acid and mefenamic acid the 10(-4)M range. The effect of other NSAIDs was seen with an IC(50) greater than 10(-3)M. A statistically significant linear correlation between the values of LDH efflux and prostaglandin E(2) was found for NSAIDs whose IC(50) of cytoprotection (LDH efflux) was below 10(-4)M. The concentration of interleukin 10 was increased with nimesulide, celecoxib, meloxicam, flurbiprofen, ibuprofen and diclofenac. Flurbiprofen and diclofenac significantly inhibited the production of lipid peroxides. The increase in brain nitrite levels was significantly reduced with celecoxib, flurbiprofen, diclofenac and salicylic acid. Concentrations of 3-nitrotyrosine were significantly reduced with celecoxib, flurbiprofen, ibuprofen, salicylic acid and ketorolac. In conclusion, NSAIDs with the greatest cytoprotective effect (nimesulide, celecoxib and meloxicam) may exert their effect mainly through the blockade of cyclooxygenase-2 (COX-2) activity. Other compounds with neuroprotective activity may complement their lower anti-COX-2 effect with a slight increase in interleukin 10 and reduced oxidative and nitrosative stress in our model of hypoxia-reoxygenation in rat brain slices.

Effects of hydroxytyrosol and hydroxytyrosol acetate administration to rats on platelet function compared to acetylsalicylic acid.

Virgin olive oil (VOO) contains the polyphenols hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC). This study investigated the antiplatelet effect of HT and HT-AC in healthy rats and compared their effects to acetylsalicylic acid (ASA). All compounds were administered orally for 7 days. HT and HT-AC inhibited platelet aggregation in whole blood, with a 50% inhibitory dose (ID50) of 48.25 mg/kg per day for HT, 16.05 mg/kg per day for HT-AC, and 2.42 mg/kg per day for ASA. Platelet synthesis of thromboxane B2 was inhibited by up to 30% by HT and 37% by HT-AC; the ID50 of this effect for ASA was 1.09 mg/kg per day. Vascular prostacyclin production was inhibited by up to 27.5% by HT and 32% by HT-AC; the ID50 of this effect for ASA was 6.75 mg/kg per day. Vascular nitric oxide production was increased by up to 34.2% by HT, 66% by HT-AC, and 64% by ASA. We conclude that HT and HT-AC administered orally inhibited platelet aggregation in rats and that a decrease in thromboxane synthesis along with an increase in nitric oxide production contributed to this effect.

Effects of dexibuprofen on platelet function in humans: comparison with low-dose aspirin.

BACKGROUND: The aim of the current study is to evaluate the antiplatelet effect of dexibuprofen in healthy volunteers in comparison with low-dose aspirin. METHODS: Healthy volunteers (n = 12) were treated in a crossover manner with 100 mg daily aspirin or with 800 mg daily dexibuprofen. Blood samples were obtained within 24 h; 3, 7, and 14 days after repeated doses; and 24 h after the last dose. In each sample, the authors measured platelet aggregation, thromboxane B2, 6-keto-prostaglandin F1alpha, and nitric oxide. RESULTS: The antiplatelet effect of dexibuprofen (maximal inhibition of aggregation was 48-55% for adenosine diphosphate and 90-95% for collagen and arachidonic acid) was equal to the effect of aspirin. The main difference between the two drugs was in the degree of recovery of platelet function. The effect of aspirin persisted for 24 h after the last dose (remaining inhibition 50%, respect to the pretreatment value), whereas platelet aggregation had returned to baseline pretreatment values within 24 h after dexibuprofen was stopped. CONCLUSIONS: Both aspirin and dexibuprofen inhibited platelet function with a similar intensity, but dexibuprofen exerted a reversible effect for 24 h after the last dose.