Cuprizone, White Matter,and Schizophrenia?

It's interesting that this cuprizone model which is most often used for the toxin in a multiple sclerosis model is also used here as a Psychiatric Schizophrenia model.Other abnormal behavioral models might also apply. The overlap with Cuprizone/Hexachlorophene should also be recognized since both are toxic to oligodendrocytes.There is also some overlap to areas of the brain (eg cerebellum, hippocampus)that are targets of their toxicity.


Schizophrenia Research
Volume 106, Issues 2-3, December 2008, Pages 182-191
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Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse
Yanbo Zhanga, b, Haiyun Xuc, Wengao Jiangd, Lan Xiaoe, Bin Yanb, Jue Heb, Yanlin Wangb, Xiaoying Bib, Xiaokun Lid, Jiming Kongf, , and Xin-Min Lia, b, ,

Abstract
Recent human studies employing new magnetic resonance imaging techniques and micro-array analyses feature schizophrenia as a brain disease with alterations in white matter (WM), which is mainly composed of oligodendrocytes (OLs) and their processes wrapping around neuronal axons. To examine the putative role of OLs in the pathophysiology and treatment of schizophrenia, animal studies are essential. In the present study, C57BL/6 mice were given 0.2% cuprizone (CPZ) in their diet for five weeks during which they drank distilled water without or with quetiapine (QTP, 10 mg/kg). The mice fed with normal chow were used as controls. CPZ is a copper chelator and has been reported to induce consistent demyelination in the brain of C57BL/6 mouse by specifically damaging OLs. QTP is an atypical antipsychotic widely used in the treatment of schizophrenia and other psychotic disorders. In accordance with previous studies, CPZ-exposed mice showed pervasive myelin breakdown and demyelination. The amount of myelin basic protein (MBP) in the cerebral cortex was decreased by CPZ-exposure as shown in Western-blot analysis. In addition, the demyelinated sites were teemed with activated microglia and astrocytes but a few myelin forming OLs. Moreover, the activity of copper-zinc superoxide dismutase decreased in the cerebral cortex of CPZ-exposed mice. However, all of these pathological changes in WM were either prevented or alleviated in CPZ-exposed mice co-administered with QTP. These results suggest that the CPZ-exposed C57BL/6 mouse is a potential animal model to study possible roles of OLs in the pathogenesis and treatment of schizophrenia.

Magnetic resonance imaging (MRI) studies using new techniques such as magnetic transfer imaging and diffusion tensor imaging provide consistent evidence showing white matter (WM) pathology in schizophrenic brains ([Ardekani et al., 2003], [Buchsbaum et al., 2006], [Kubicki et al., 2005] and [Minami et al., 2003]). Genome-wide expression analyses on brain tissues of patients with schizophrenia show dysregulation of genes related to oligodendrocyte (OL) function and myelination ([Hakak et al., 2001], [McCullumsmith et al., 2007] and [Tkachev et al., 2003]). Furthermore, a prominent and significant reduction in the number of perineuronal OLs in sublayers IIIa, IIIb, and IIIc of the prefrontal cortex of patients with schizophrenia has been reported (Vostrikov et al., 2007), and patients with WM disorders experience a host of psychotic symptoms (Hyde et al., 1992). These human studies strongly suggest a prominent role for OLs and brain demyelination in the pathophysiology of schizophrenia.....

To examine the putative role of OLs in the pathophysiology of schizophrenia, animal studies are essential. In our previous study (Xiao et al., 2008) we tested effects of quetiapine (QTP) on the cuprizone (CPZ)-exposed mice, which is an animal model of multiple sclerosis (MS). As a copper chelator, CPZ induces consistent demyelination in the brain of C57BL/6 mouse by specifically damaging OLs ([Matsushima and Morell, 2001] and [Morell et al., 1998]), without affecting peripheral nerves (Komoly, 2005). Quetiapine is a new atypical antipsychotic drug that is widely used in the treatment of schizophrenia and other psychotic disorders. It effectively alleviates positive and negative symptoms, as well as cognitive impairment, in patients with schizophrenia. We found that chronic administration of QTP effectively block the myelin breakdown in the cerebral cortex (CTX) and concomitant spatial working memory impairment in the CPZ-exposed C57BL/6 mice (Xiao et al., 2008)...

Discussion
The finding shown in our previous study (Xiao et al., 2008) that chronic administration of QTP attenuates myelin breakdown in the CTX of CPZ-exposed mice was confirmed in the present study, indicated by the results in Fig. 2. In addition, we performed Western blot analysis which provided further evidence (Fig. 2e) that CPZ exposure decreases the amount of MBP of the CTX and chronic administration of QTP attenuates this decrease in MBP (Fig. 2e). Moreover, LFB-PAS stain provided complementary evidence supporting the above conclusion by showing the most severe demyelination in the CC of CPZ-exposed mice and less severe demyelination in the CC of mice co-administered with CPZ and QTP ...

Although schizophrenia has nothing related to CPZ, the WM pathology seen in brains of CPZ-exposed mice is certainly heuristic for us to understand schizophrenia. First, these CPZ-induced changes are reminiscent of the results of recent neuroimage studies in patients with schizophrenia ([Cheung et al., 2008], [Rotarska-Jagiela et al., 2008] and [Zou et al., 2008]). These studies reported reduced FA (fractional anisotropy, an index used to characterize the integrity of WM tracts) in the bilateral anterior limb of the internal capsule of neuroleptic-naïve schizophrenia patients (Zou et al., 2008), decreased FA and decreased volume of the whole CC in chronic paranoid schizophrenia patients (Rotarska-Jagiela et al., 2008), and lower FA in the CC and other WM of never-medicated, first-episode schizophrenia (Cheung et al., 2008). Second, CPZ-exposed mice not only have WM pathology but also display abnormal behaviours mimicking certain schizophrenia symptoms (Xu et al., in press).
It should be pointed out that the protective effects of QTP on CPZ-induced WM pathology shown in the present study do not necessarily suggest that other antipsychotics have similar effects. In fact, there are inconsistent reports regarding effects of antipsychotics on brain WM. For example, Molina et al. (2005) reported that atypical neuroleptics increased gray matter (GM) but decreased WM....

N.B. Bolding is most often by me.
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