Effects of clioquinol on memory impairment and the neurochemical modifications induced by scrapie infection in golden hamsters.
ABSTRACT Prion protein (PrP) is a glycoprotein expressed on the surface of neurons and glial cells. Its pathological isoform (PrP(res)) is protease resistant, and involved in the pathogenesis of a number of transmissible encephalopathies (TSEs). One common feature of neurodegenerative diseases, including TSEs, is oxidative stress, which may be responsible not only for the dysfunction or death of neuronal cells, but also cognitive deficits. Clioquinol (5-chloro-7-iodo-8-quinolinol) chelates zinc and copper, which are involved in the deposition of amyloid plaques and acts as an antioxidant; increased lipid peroxidation has also been demonstrated in the early phases of PrP propagation. The aim of this study was to investigate the effects of clioquinol on the changes in motor and cognitive behaviours induced by scrapie infection, as well as its effects on oxidative stress and the neurotransmitters known to be involved in motor and cognitive functions. The results show that clioquinol counteracts the massive memory deficit induced by scrapie infection. This effect is not paralleled by neurochemical changes because the levels of all of the biogenic amines and their metabolites were reduced despite clioquinol treatment. The main biochemical change induced by clioquinol was a marked reduction in lipid peroxidation at all time points. The antioxidant effect of clioquinol can reduce functional impairment and thus improve memory, but clioquinol does not reduce PrP deposition or synapse loss, as indicated by the unchanged Western blot, histopathological and histochemical findings.
- SourceAvailable from: Hideko SoneLearning Disabilities, 03/2012; , ISBN: 978-953-51-0269-4
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ABSTRACT: AIMS: The misfolding and the aggregation of specific proteins are key features of neurodegenerative diseases, specifically Transmissible Spongiform Encephalopathies (TSEs). In TSEs, neuronal loss and inflammation are associated with the accumulation of the misfolded isoform (PrP(sc)) of the cellular prion protein (PrP(c)). Therefore we tested the hypothesis that augmenting a natural anti-inflammatory pathway mediated by epoxygenated fatty acids (EpFAs) will delay lethality. EpFAs are highly potent but enzymatically labile molecules produced by the actions of a number of cytochrome P450 enzymes. Stabilization of these bioactive lipids by inhibiting their degradation mediated by the soluble epoxide hydrolase (sEH) results in potent anti-inflammatory effects in multiple disease models. MAIN METHODS: Mice were infected with the mouse-adapted RML strain of scrapie by intracerebral or intraperitoneal routes. Animals received the sEH inhibitor, by oral route, administrated in drinking water or vehicle (PEG400). Infected mice were euthanized at a standard clinical end point. Histopathological, immunohistochemical and Western blot analyses of brain tissue confirmed the presence of pathology related to prion infection. KEY FINDINGS: Oral administration of the sEHI did not affect the very short survival time of the intracerebral prion infection group. However, mice infected by intraperitoneal route and treated with t-AUCB survived significantly longer than the control group mice (p < 0.001). SIGNIFICANCE: These findings support the idea that inhibition of sEH or augmentation of the natural EpFA signalling in the brain offers a potential and different route to understand prion diseases and may become a therapeutic strategy for diseases involving neuroinflammation.Life sciences 05/2013; · 2.56 Impact Factor
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ABSTRACT: Clioquinol (CQ), a metal chelator, has gained renewed attention due to its ability to modulate metal homeostasis in neurodegenerative disorders such as Alzheimer's disease. To investigate the protective effects of a wide range of concentrations of CQ on two human neuroblastoma cell lines (IMR-32 and SKN-AS) and to develop and characterize a new controlled release system of CQ consisting of biodegradable microspheres. H(2)O(2) (400 μM) adequately induced death cell in IMR-32 and SKN-AS cell lines thereby resulting in a useful model for neuroprotective studies. CQ (20-50 μM) induced a potent and robust protective effect against peroxide-mediated oxidative stress in human neuronal-like cells (SKN-AS) determined by both MTT and flow cytometry (cell viability). These results were also confirmed by means of reactive oxygen species (ROS) production. Biodegradable poly(dl-lactic-co-glycolic acid) (PLGA) resomers assayed for microspheres preparation were PLGA-502 and PLGA-502H. Optimization by using an experimental design resulted in a formulation prepared with CQ (112 mg) and PLGA-502H (400 mg). With this formulation, mean encapsulation efficiency of 82.37% ± 6.67% and, zero-order release rate of 58 ± 3µg CQ/day/10 mg microspheres between Days 10 and 35 were obtained. We have developed a promising formulation for the treatment of Alzheimer's disease.Journal of Drug Targeting 10/2010; 19(8):637-46. · 2.77 Impact Factor