Protective effects of the antioxidant selenium on quinolinic acid‐induced neurotoxicity in rats:in vitroandin vivostudies

Abstract

Quinolinic acid (QUIN), a well known excitotoxin that produces a pharmacological model of Huntington's disease in rats and primates, has been shown to evoke degenerative events in nerve tissue via NMDA receptor (NMDAr) overactivation and oxidative stress. In this study, the antioxidant selenium (as sodium selenite) was tested against different markers of QUIN-induced neurotoxicity under both in vitro and in vivo conditions. In the in vitro experiments, a concentrationdependent effect of selenium was evaluated on the regional peroxidative action of QUIN as an index of oxidative toxicity in rat brain synaptosomes. In the in vivo experiments, selenium (0.625 mg per kg per day, i.p.) was administered to rats for 5 days, and 2 h later animals received a single unilateral striatal injection of QUIN (240 nmol/lL). Rats were killed 2 h after the induction of lesions with QUIN to measure lipid peroxidation and glutathione peroxidase (GPx) activity in striatal tissue. In other groups, the rotation behavior, GABA content, morphologic alterations, and the corresponding ratio of neuronal damage were all evaluated as additional markers of QUIN-induced striatal toxicity 7 days after the intrastriatal injection of QUIN. Selenium decreased the peroxidative action of QUIN in synaptosomes both from whole rat brain and from the striatum and hippocampus, but not in the cortex. A protective concentration-dependent effect of selenium was observed in QUIN-exposed synaptosomes from whole brain and hippocampus. Selenium pre-treatment decreased the in vivo lipid peroxidation and increased the GPx activity in QUIN-treated rats. Selenium also significantly attenuated the QUIN-induced circling behavior, the striatal GABA depletion, the ratio of neuronal damage, and partially prevented the morphologic alterations in rats. These data suggest that major features of QUIN-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that selenium partially protects against QUIN toxicity.

Systemic Levels of MMP2/TIMP2 and Cardiovascular Risk in CAPD Patients

“…More recently, we demonstrated that both KYN and its metabolite, QA, were positively associated with oxidative status and a surrogate marker of CVD, such as intima-media thickness (IMT) in the population of uremic patients [16]. Our observation is in the line with the previous results of Santamaria et al [17,18], who demonstrated that QA was a generator of reactive oxygen species (ROS) in the brain. These data suggest that SOX-generating KYN metabolites could be a new predictor of atherosclerosis in uremia.…”

“…Paradoxically, the inhibitor TIMP-2 is necessary for MMP-2 activation [27], and the expression of MMP-2 and TIMP-2 overlaps in vascular tissues [4]. On the other hand, Santamaria et al [17,18] demonstrated that QA was a generator of ROS in the brain, which might, in part, be responsible for its neurotoxic properties. The above observations and the results of the present study suggest that QA, by generating SOX, could affect MMP-2 levels in the blood of CAPD patients, particularly those with CVD.…”

Quinolinic acid induces NMDA receptor-mediated lipid peroxidation in rat brain microvessels

“…The fluorescence in the chloroform layer was measured as described earlier. 16 In the binding studies, the microvessels, prepared as above, were pooled from prosencephala of 24 rats, disrupted by additional homogenization using Ultra-Turax T8 (IKA Labortechnik, Germany) in twice-distilled water at 2-4°C and centrifuged at 48,000 g for 20 min. The pellets were resuspended and aliquots (0.1 ml) of the suspension (100-200 µg protein) were incubated at 4°C for 30 min in the presence of 10 nM L-…”

Involvement of quinolinic acid in aids dementia complex

“…Importantly, there are already preliminary data of the efficacy of deprenyl in ADC (Turchan et al, 2003). Santamaria et al showed recently that copper at low doses (Santamaria et al, 2003a) and selenium (antioxidant effect) (Santamaria et al, 2003b) significantly decreases QUIN neurotoxicity. Another molecule, the kappa opioïd ligand U50,488 may have therapeutic potential in ADC by attenuating microglial production of QUIN (Chao et al, 2000).…”