No abstract

As neuroinflammatory processes are involved in the pathogenesis of Parkinson's disease (PD), we achieved the longitudinal evaluation of them in parallel with the modifications of dopaminergic function at several time-points after 6-hydroxydopamine (6-OHDA) lesion in the rat mimicking an early stage of PD. After unilateral intrastriatal 6-OHDA administration, we quantified the temporal evolution of the 18 kDa translocator protein (TSPO), TH-immunoreactivity and dopamine transporters in the striatum and substantia nigra pars compacta (SNc) from 3- to 56-days postlesion (dpl). Increased binding of TSPO ligands used, i.e., [(3)H]PK11195 and [(125)I]CLINDE, was observed in the lesioned striatum at 3, 7, and 14 dpl, followed by a progressive return to the basal level at 56 dpl. The binding profile in the SNc showed progressive binding beginning at 3 dpl, peaking at 14 dpl, and progressively decreasing until 56 dpl. In this model, the neuroinflammatory and neurodegenerative processes occurred concomitantly. The transitory occurrence of microglial activation could be involved in the lasting installation of dopaminergic neuron loss.

These results demonstrate that CLINDE is suitable for TSPO in vivo SPECT imaging to explore their involvement in neurodegenerative disorders associated with microglial activation.

No abstract

We sought to investigate the apoptosis-inducing activities of quercetin, Siamois 1, and Siamois 2 against invasive estrogen-receptor negative MDA-MB 435 cells xenografted in athymic nude mice. This study clearly demonstrated that these compounds exhibited apoptosis-inducing activities in cell culture system. Quercetin (20 microg/mL), Siamois 1 (100 microg/mL), and Siamois 2 (200 microg/mL) can induce apoptotic cell death by 40 +/-5%, 44 +/- 14 %, and 31 +/- 13 %, respectively. Two-fold of IC50 of these compounds were clearly found to induce apoptosis in breast tumor tissue which can be determined by 99mTc-Annexin V scintigraphy and histological staining. This is the first report that the apoptosis-inducing effects of quercetin, Siamois 1 and Siamois 2 on the MDA-MB 435 cell in vitro were effectively extrapolated to the in vivo situation. These compounds might be considered as a simple dietary supplement and with further clinical investigation for their use as a nutrition-based intervention in breast cancer treatment.

The overexpression of two membrane glycoproteins, P-glycoprotein and multidrug-resistance protein (MRP 1 ) is a major cause of resistance to chemotherapeutic agents in the treatment of human cancers. Both proteins confer a similar multidrug-resistant (MDR) phenotype. Tc-MIBI, a myocardial imaging agent, which is also useful for the detection of a variety of tumours, has been shown to be a substrate for P-glycoprotein and MRP 1 . It thus may provide additional information about the P-glycoprotein and MRP 1 status of tumour cells.In order to obtain information on the substrate specificity of these proteins, we have studied the transport kinetics of Tc-MIBI in two cell lines, K562/ADR and GLC 4 /ADR, which overexpress P-glycoprotein and MRP 1, respectively. The mean active efflux coefficient ka, which is proportional to the ratio of maximal efflux rate V M to the apparent Michaelis-Menten constant K m , used to characterise the efficiency of the active efflux, was very similar being 1.9 Ϯ0.6ϫ10 Ϫ11 s Ϫ1 · cells · ml and 1.3Ϯ 0.5ϫ10 Ϫ11 s Ϫ1 · cells · ml for drug-resistant K562 and GLC4, respectively. These values are 50Ϫ100-times lower than for daunorubicin and other anthracycline derivatives, strongly suggesting that the efficiency of both transporters to pump Tc-MIBI is by far less than that to efflux anthracyclines. Our data show that (a) P-glycoprotein and MRP transporter efficiencies to wash out Tc-MIBI are similar, in spite of a different suspected mechanism of its transport and (b) that both transporters are less efficient to pump Tc-MIBI than to pump anthracyclines (the k a parameter is about 100-times lower for TC-MIBI than for anthracycline).Keywords : multidrug-resistance; P-glycoprotein; multidrug-resistance protein; technetium hexakis(methoxyisobutylisonitrile).Cancer cells lines treated in vitro with one of a group of (Hughes, 1994), which have ATP-binding sites (Cornwell et al., amphipathic cytotoxic drugs frequently assumes a multidrug-re-1987; McGrath et al., 1989). In the case of P-glycoprotein, there sistant (MDR) phenotype (Bradley and Ling, 1988), the cells is considerable experimental evidence that the protein causes becoming resistant to a range of structurally and functionally resistance by transporting neutral or positively charged drugs out unrelated drugs. The classical form of drug resistance is caused of the cell (Gottesman and Pastan, 1993). The mechanism by by enhanced expression of the mdr 1 gene, which encodes the P-which MRP 1 mediates reduced drug accumulation in resistant glycoprotein. P-glycoprotein is an ATP-dependent drug exporter cells is less well understood. However, it has been clearly establocated in the plasma membrane of various cell types (Gottes-lished that it has the properties of an organic anion transporter man and Pastan, 1993). Recently, a second ATP-dependent (GS-X pump) (Loe et al., 1996; Leier et al., 1994 ; Müller et transporter of anti-tumour drugs has been identified in mamma-al., 1994). Despite considerable overlap in substrate specificity lian cells, the...

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the nigro‐striatal pathway. Interestingly, it has already been shown that an intracerebral administration of neuropeptide Y (NPY) decreases the neurodegeneration induced by 6‐hydroxydopamine (6‐OHDA) in rodents and prevents loss of dopamine (DA) and DA transporter density. The etiology of idiopathic PD now suggest that chronic production of inflammatory mediators by activated microglial cells mediates the majority of DA‐neuronal tissue destruction. In an animal experimental model of PD, the present study shows that NPY inhibited the activation of microglia evaluated by the binding of the translocator protein (TSPO) ligand [3H]PK11195 in striatum and substantia nigra of 6‐OHDA rats. These results suggest a potential role for inflammation in the pathophysiology of the disease and a potential treatment by NPY in PD.

Natural products from plants such as flavonoids are potential drugs to overcome multidrug resistance (MDR) in cancer treatments. However, their modes of action are still unclear. In this study, the effects of quercetin on mitochondrial membrane potential (DeltaPsim) change as well as quercetin's ability to induce apoptosis and inhibit Pgp-mediated efflux of 99mTc-MIBI in K562/adr cells were investigated. Quercetin exhibits cytotoxicity against erythroleukemic cells: IC50 are 11.0 +/- 2.0 micromol/L and 5.0 +/- 0.4 micromol/L for K562 and K562/adr, respectively. Quercetin induces cell death via apoptosis in both K562 and K562/adr cells and does not inhibit Pgp-mediated efflux of 99mTc-MIBI. Quercetin (10 micromol/L, 3 h) and etoposide (100 micromol/L, 24 h) induce similar levels of apoptosis in K562 and K562/adr cells. Quercetin induces an increase followed by a decrease in |DeltaPsim| value depending on its concentration. A decrease in the |DeltaPsim| value is associated with an increase in the percentage of early apoptotic cells. It is clearly shown that quercetin results in a spontaneous DeltaPsim change during apoptotic induction. Therefore, quercetin is potentially an apoptotic-inducing agent, which reacts at the mitochondrial level.