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.
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ABSTRACT: There is a great deal of evidence to support a pathogenic role of oxidative stress in Alzheimer's disease (AD), but the sources of reactive oxygen species have not been directly demonstrated. In this study, using a novel in situ detection system, we show that neurofibrillary tangles and senile plaques are major sites for catalytic redox reactivity. Pretreatment with deferoxamine or diethylenetriaminepentaacetic acid abolishes the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions. Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Although DAB oxidation can also detect peroxidase activity, this was inactivated by H2O2 pretreatment before use of DAB, as shown by a specific peroxidase detection method. Model studies confirmed the ability of certain copper and iron coordination complexes to catalyze the H2O2-dependent oxidation of DAB. Also, the microtubule-associated protein tau, as an in vitro model for proteins relevant to AD pathology, was found capable of adventitious binding of copper and iron in a redox-competent manner. Our findings suggest that neurofibrillary tangles and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment.Journal of Neurochemistry 01/2000; 74(1):270-9. · 3.97 Impact Factor
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ABSTRACT: Scrapie-infected hamsters were tested for spontaneous motor activity and passive avoidance at various times after infection. After testing, some animals were killed and their whole brains assayed for norepinephrine, dopamine, serotonin and their metabolites. The apparent rate of turnover was estimated in terms of metabolite/amine concentrations. After 70 days, there was a decrease in passive avoidance and dopamine and serotonin. Passive avoidance correlated with the apparent rate of turnover of dopamine, whereas motor activity correlated with that of serotonin and dopamine.Brain Research 10/2003; 984(1-2):237-41. · 2.88 Impact Factor
- Veterinary Research Communications 07/2006; 30:253-255. · 1.08 Impact Factor