Biomedical subjects

Jean-Paul Tillement

Publications and source records attributed to Jean-Paul Tillement.

6 recordsLinked to original sources

PubMed2003

Anoxia-reoxygenation-induced cytochrome c and cardiolipin release from rat brain mitochondria.

Rat brain mitochondria were successively submitted to anoxia and reoxygenation. The main mitochondrial functions were assessed at different reoxygenation times. Although the respiratory control ratio decreased, the activity for each one of the enzymes participating in the respiratory chain was not affected. However, during reoxygenation, mitochondrial membrane lipoperoxidation quickly increased and was proportional to the decrease seen in membrane fluidity. Under the same conditions, cytochrome c and cardiolipin were released from mitochondria and their rate of release increased with reoxygenation time. The release of cytochrome c and cardiolipin was followed by the collapse of the membrane potential and it was not inhibited by cyclosporin A. Addition of the antioxidant alpha-tocopherol abolished all these reoxygenation-induced changes. These data indicate that, in this model, reoxygenation promotes the uncoupling of respiratory chain, and cytochrome c and cardiolipin releases. These events are not related to the membrane potential collapse but to an oxidative stress.

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PubMed2003

Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.

1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.

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PubMed2002

Resveratrol-induced limitation of dysfunction of mitochondria isolated from rat brain in an anoxia-reoxygenation model.

Resveratrol protection on the main functions of purified rat brain mitochondria submitted to anoxia-reoxygenation was investigated. Resveratrol (<0.1 microM) reversed partly (23.3%) the respiratory control ratio (RCR) decrease by protecting both states 3 and 4. This effect was both observed when resveratrol was added before anoxia or reoxygenation. Resveratrol fully inhibited the release of cytochrome c in a concentration-dependent manner and significantly decreased the superoxide anion (O2(0-)) production at a concentration of 1 nM. The mitochondrial membranes damaged after the anoxia-reoxygenation were partly protected (about 70%) by resveratrol at 0.1 microM. The oxygen consumption of mitochondria in presence of NADH and cytochrome c was significantly inhibited by resveratrol with a low EC50 of 18.34 pM. Resveratrol inhibited the CCCP-induced uncoupling from about 20%. The effects of resveratrol on oxidative phosphorylation parameters were also investigated in rats after pretreatment (0.4, 2 and 10 mg/kg/day) for one week. After the isolation of brain mitochondria, the RCR was significantly less decreased in the resveratrol group compared to the control group. These results showed that resveratrol could preserve the mitochondrial functions with at least three mechanisms: antioxidant properties, action on complex III and a membrane stabilizing effect.

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PubMed2002

Evidence for sigma-1-like receptors in isolated rat liver mitochondrial membranes.

1. Sigma (sigma) receptors have generated a great deal of interest on the basis of their possible roles in various pathologies, including cytoprotection. Although the exact function of sigma-1 (sigma(1)) receptors is not yet known, their role in the regulation of intracellular Ca(2+) levels and sterol biosynthesis, functions that could be assigned to mitochondria, are the only mechanisms described. 2. Using preparations of purified rat liver and brain mitochondria we demonstrate herein the presence of sigma-like binding sites. [(3)H](+)-pentazocine, a sigma(1) radioligand was used to label these sites. 3. In the liver, [(3)H](+)-pentazocine labelled one class of binding sites with high affinity (K(d)=3 nM), similar to that observed in liver microsomes and synaptic membranes. These sites were located on the outer mitochondrial membranes and displayed high affinity for other sigma(1) ligands namely, haloperidol, ifenprodil, carbetapentane or 1,3-di(2-tolyl)guanidine (DTG). 4. The presence of sigma(1) receptors on liver mitochondria was confirmed using double fluorescence immunostaining. 5. [(3)H](+)-pentazocine binding sites were also found on brain mitochondria but they appeared pharmacologically distinct to the liver ones as [(3)H](+)-pentazocine and typical sigma(1) ligands displayed lower affinities for these sites. Nevertheless, [(3)H](+)-pentazocine binding on both liver and brain mitochondria was modulated by progesterone, a putative endogenous ligand for sigma receptors. 6. Our data demonstrates the presence of [(3)H](+)-pentazocine binding sites with pharmacological characteristics identical to sigma(1) receptors on rat liver mitochondrial membranes. The pharmacological significance of these sites and their role on mitochondrial function remain unknown.

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PubMed2002

Blood distribution of levocetirizine, a new non-sedating histamine H1-receptor antagonist, in humans.

The aim of the present study was to determine (1) the extent of levocetirizine binding to human blood cells, plasma and individual plasma proteins; (2) the parameters for levocetirizine binding to individual plasma proteins both at their physiological concentrations and, for human serum albumin (HSA), at a lower saturating concentration; and (3) to simulate levocetirizine distribution in human blood using the information obtained at physiological haematocrit (H) for blood cells and at physiological concentrations for individual plasma proteins. The nature of the main binding sites of HSA, i.e. site I (warfarin) and site II (diazepam), preferentially involved in levocetirizine binding was also investigated. Over the range of therapeutic concentrations and multiples thereof, levocetirizine is extensively bound to blood components, the free fraction remaining constant (6.45%) and the fraction bound to blood cells and to plasma proteins accounting for 27.43 and 66.11%, respectively. The binding of levocetirizine to HSA in the presence of physiological concentrations of non-esterified fatty acids (NEFAs) is the main interaction of levocetirizine in blood (50.68% of overall blood binding). This interaction is fatty acid sensitive, with decreasing concentrations of NEFA increasing the amount of bound drug and vice versa. Levocetirizine is also bound to alpha1-acid-glycoprotein and high-density lipoproteins (5.17 and 6.89% of overall blood binding, respectively). The displacement of levocetirizine by diazepam is consistent with the binding of this drug to HSA at site II, as diazepam is a specific marker for this site. The binding of levocetirizine to HSA at site II being characterized by a low association constant, other drugs sharing the same site with high association constants cannot displace levocetirizine except at very high plasma concentrations. In any case, at therapeutic concentrations of levocetirizine and at physiological protein concentrations, the observation that none of the levocetirizine binding proteins is saturated suggests that very little or no variation of the free fraction will occur although a different distribution of its bound forms is possible.

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PubMed2000

Trimetazidine reduces renal dysfunction by limiting the cold ischemia/reperfusion injury in autotransplanted pig kidneys.

Ischemia/reperfusion injury leads to delayed graft function, which is a major problem in kidney transplantation. This study investigated the effects of adding trimetazidine (TMZ) to the perfusate of cold-stored kidneys on the function of reperfused autotransplanted pig kidney. The left kidney was removed and cold-flushed with Euro-Collins (EC), or University of Wisconsin (UW) solutions with or without 10(-6)M TMZ and stored for 48 h at 4 degrees C. The kidneys were then autotransplanted and the contralateral kidneys were removed. Several parameters were analyzed over the 14 d after transplantation. The survival rate was 57% in pigs transplanted with kidneys cold-flushed with UW and 43% for those flushed with EC solution; it was 100% for pigs having kidneys cold-flushed with TMZ-supplemented UW and EC solutions. The functions of the transplanted kidneys were also better preserved after cold flush with TMZ-supplemented solutions than with TMZ-free solutions. Creatinine clearance was higher and the urinary excretion of trimethylamine-N-oxide and dimethylamine, used as markers of renal medulla injury, were lower in animals transplanted with kidneys cold-flushed with TMZ-supplemented solutions than with TMZ-free solutions. The cytoprotective action of TMZ also reduced interstitial and peritubular inflammation and the numbers of infiltrating mononuclear CD45+and CD3+ T cells. These results indicate that the tissue damage due to ischemia/reperfusion injury may be prevented, at least in part, by adding TMZ to preservation solutions.

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