Effects of clioquinol on memory impairment and the neurochemical modifications induced by scrapie infection in golden hamsters

Department of Pharmacology, Chemotherapy and Medical Toxicology, School of Medicine, Milano, Italy.
Brain research (Impact Factor: 2.84). 08/2009; 1280:195-200. DOI: 10.1016/j.brainres.2009.05.031
Source: PubMed


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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Available from: Daniela Braida, Jan 23, 2015
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    • "The etiopathology of prion diseases shares a number of characteristics with Alzheimer's Disease (AD) in which protein misfolding and the deposition of amorphous aggregates or amyloid fibrils in the central nervous system (CNS) lead to microglial activation, neuroinflammation and neurotoxicity (Checler and Vincent, 2002; Dickson, 1997; Ronga et al., 2006). While other authors have approached therapeutic intervention by using various anti-prionic drugs here we targeted neuroinflammation as a strategy to limit the progression of the disease (Bareggi et al., 2009; Magri et al., 2005; Poli et al., 2004). Large scale clinical trials demonstrated no benefit in inhibiting the major pro-inflammatory proteins cox-1 (cyclooxygenase-1) or cox-2 (cyclooxygenase-2). "
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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 signaling 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; 92(23). DOI:10.1016/j.lfs.2013.04.014 · 2.70 Impact Factor
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    • "Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline; CQ) forms lipophilic chelates with cations such as Zn2+ and Cu2+ and has a relatively weak affinity for zinc (Kd, approximately 1×10−7 M). CQ transiently decreases Zn2+ levels without interfering with the tightly bound zinc pool, such as zinc fingers and numerous catalytic enzymes, which are essential for cellular functions [27], [28], [29]. Acute exposure to CQ affects object recognition memory 24 h after training, suggesting that transient lack of Zn2+ is involved in object recognition memory deficit [30]. "
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    ABSTRACT: The translocation of synaptic Zn(2+) to the cytosolic compartment has been studied to understand Zn(2+) neurotoxicity in neurological diseases. However, it is unknown whether the moderate increase in Zn(2+) in the cytosolic compartment affects memory processing in the hippocampus. In the present study, the moderate increase in cytosolic Zn(2+) in the hippocampus was induced with clioquinol (CQ), a zinc ionophore. Zn(2+) delivery by Zn-CQ transiently attenuated CA1 long-term potentiation (LTP) in hippocampal slices prepared 2 h after i.p. injection of Zn-CQ into rats, when intracellular Zn(2+) levels was transiently increased in the CA1 pyramidal cell layer, followed by object recognition memory deficit. Object recognition memory was transiently impaired 30 min after injection of ZnCl(2) into the CA1, but not after injection into the dentate gyrus that did not significantly increase intracellular Zn(2+) in the granule cell layer of the dentate gyrus. Object recognition memory deficit may be linked to the preferential increase in Zn(2+) and/or the preferential vulnerability to Zn(2+) in CA1 pyramidal neurons. In the case of the cytosolic increase in endogenous Zn(2+) in the CA1 induced by 100 mM KCl, furthermore, object recognition memory was also transiently impaired, while ameliorated by co-injection of CaEDTA to block the increase in cytosolic Zn(2+). The present study indicates that the transient increase in cytosolic Zn(2+) in CA1 pyramidal neurons reversibly impairs object recognition memory.
    PLoS ONE 12/2011; 6(12):e28615. DOI:10.1371/journal.pone.0028615 · 3.23 Impact Factor
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    • "In neurodegenerative disorders, neuronal cell death can be induced by ROS via a wide range of diierent pathways. e chemical origin of the majority of hydroxy (OH), the most import powerful oxidant, is the reaction of H 2 O 2 with redox-active metal as copper and iron, high concentrations of which are normally found in the brain region most susceptible to AD neurodegeneration (Bareggi et al., 2009). For this, in order to produce oxidative stress in SKN-AS cells, thereby resulting in cell death, we have used H 2 O 2 as neurotoxin that has been tested in a wide concentration range (100–900 µM). "
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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. DOI:10.3109/1061186X.2010.523789 · 2.74 Impact Factor
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