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
________________________________________
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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Thursday, June 10, 2010
Saturday, November 14, 2009
Cuprizone and Hexachlorophene Comparisons
In this blog I'd like to make a comparison between two neurotoxins: Hexachlorophene and Cuprizone. There are both similarities and differences. The importance of the similarity of their effects I think have been ignored.
Purvis (1991) showed that both Hexachlorophene and Cuprizone caused vacuoles (spaces) in the white matter of the rats. One important difference between Hexachlorophene and Cuprizone is that there is extensive research that hexachlorophene is a white matter neurotoxin in humans, especially babies. That should make hexachlorophene a focus of animal and human research.
Instead, as you will see, it is Cuprizone and its effect on the white matter of mice that has been the focus of extensive research. One area of research that is most interesting is the use of the Cuprizone behavior model for psychiatric research.
Particularly interesting is the use of Saraquel/Quetiapine as an effective treatment for the effects of cuprizone. Wouldn't this also be true with the effects of hexachlorophene on the vacuoles of the white matter of the human brain?
First, the direct comparison:
Hum Exp Toxicol. 1991 Nov;10(6):439-44.
A comparison of spongiosis induced in the brain by hexachlorophene, cuprizone and triethyl tin in the Sprague-Dawley rat.
Purves DC, Garrod IJ, Dayan AD.
DH Department of Toxicology, St Bartholomew's Hospital Medical College, London, UK.
The effect of hexachlorophene (HCP; 2,2'-methylenebis(3,4,6-trichlorophenol), cuprizone (CPZ; bicyclohexone oxaldihydrazone) and triethyl tin (TET; triethyl tin sulphate) in producing vacuoles in the brain of the Sprague-Dawley rat has been quantified by image analysis of the extent of the spongy change in the white matter.
Also,there was an interesting finding that cuprizone was more effective in causing vacuoles in mice than in rats. Hexachlorophene was far more efective than cuprizone in harming the white matter of rats. There were other aspects (eg tumors) of the research I have not noted here.
Cuprizone models
Here are some research examples of the use of Cuprizone as a human behavior model:
Behav Neurosci. 2009 Apr;123(2):418-29.
Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone.
Xu H, Yang HJ, Zhang Y, Clough R, Browning R, Li XM.
School of Medicine, Southern Illinois University Carbondale, Carbondale, IL 62901, USA. hxu@siumed.edu
C57BL/6 mice were given 0.2% cuprizone (CPZ) for 2 to 6 weeks while controls ate the same diet without CPZ. At various time points the animals were subjected to behavioral tests and their brains were analyzed...... inhibition, suggesting an increase in central nervous system activity and impaired sensorimotor gating. In addition, they showed lower activities of monoamine oxidase and dopamine beta hydroxylase in the hippocampus and prefrontal cortex, and had higher dopamine but lower norepinephrine levels in the prefrontal cortex. Mice exposed to CPZ for 4 to 6 weeks had less social interaction, which is an animal correlate of social withdrawal of patients with schizophrenia. Also, these CPZ-exposed mice showed evident brain demyelination, myelin break down, and loss of oligodendrocytes. At all time points the CPZ-exposed mice spent more time in the open arms of an elevated plus maze and exhibited spatial working memory impairment. These data are in line with evidence from human studies suggesting a putative role of white matter abnormality in the pathophysiology of schizophrenia. (c) 2009 APA, all rights reserved.
It is interesting to note that, like hexaclorophene, age of exposure seems important:
Prog Neuropsychopharmacol Biol Psychiatry. 2009 Aug 31;33(6):978-85. Epub 2009 May 14.
Demyelination in the juvenile period, but not in adulthood, leads to long-lasting cognitive impairment and deficient social interaction in mice.
Makinodan M, Yamauchi T, Tatsumi K, Okuda H, Takeda T, Kiuchi K, Sadamatsu M, Wanaka A, Kishimoto T.
Department of Psychiatry, Nara Medical University Faculty of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan. mmm@naramed-u.ac.jp
BACKGROUND: Dysmyelination is hypothesized to be one of the causes of schizophrenic symptoms. Supporting this hypothesis, demyelination induced by cuprizone was recently shown to cause schizophrenia-like symptoms in adult rodents [Xiao L, Xu H, Zhang Y, Wei Z, He J, Jiang W, et al. Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes. Mol Psychiatry 2008;13:697-708]. The present study asked if the timing of demyelination (i.e., juvenile period or adulthood) influenced abnormal behavior. METHODS: B57BL/6 mice were fed with 0.2% cuprizone either from postnatal day 29 (P29) to P56 (early demyelination group) or from P57 to P84 (late demyelination group).... the spatial working memory was impaired in both groups right after the cuprizone feeding ceased, consistent with previous studies, whereas only the early demyelination group exhibited impaired working memory after remyelination took place. In an open field test, social interactions were decreased in the early demyelination group, but not in the late group...CONCLUSIONS: Our findings suggest that the timing of demyelination has substantial impacts on behaviors of adult mice.
Most important for the Psychiatric model, the drug Serquel/Quetiapine seems to be an effective treatment for the cuprizone white matter neurotoxicity. here is one study:
Mol Psychiatry. 2008 Jul;13(7):697-708. Epub 2007 Aug 7.
Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes.
Xiao L, Xu H, Zhang Y, Wei Z, He J, Jiang W, Li X, Dyck LE, Devon RM, Deng Y, Li XM.
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada.
Recent neuroimaging and postmortem studies have reported abnormalities in white matter of schizophrenic brains, suggesting the involvement of oligodendrocytes in the etiopathology of schizophrenia. This view is being supported by gene microarray studies showing the downregulation of genes related to oligodendrocyte function and myelination in schizophrenic brain compared to control subjects. However, there is currently little information available on the response of oligodendrocytes to antipsychotic drugs (APDs), which could be invaluable for corroborating the oligodendrocyte hypothesis. In this study we found: (1) quetiapine (QUE, an atypical APD) treatment in conjunction with addition of growth factors increased the proliferation of neural progenitors isolated from the cerebral cortex of embryonic rats; (2) QUE directed the differentiation of neural progenitors to oligodendrocyte lineage through extracellular signal-related kinases; (3) addition of QUE increased the synthesis of myelin basic protein and facilitated myelination in rat embryonic cortical aggregate cultures; (4) chronic administration of QUE to C57BL/6 mice prevented cortical demyelination and concomitant spatial working memory impairment induced by cuprizone, a neurotoxin. These findings suggest a new neural mechanism of antipsychotic action of QUE, and help to establish a role for oligodendrocytes in the etiopathology and treatment of schizophrenia.
Here is a second study:
Schizophr Res. 2008 Dec;106(2-3):182-91. Epub 2008 Oct 19.
Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse.
Zhang Y, Xu H, Jiang W, Xiao L, Yan B, He J, Wang Y, Bi X, Li X, Kong J, Li XM.
Department of Psychiatry, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
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.
These are a small sampling of the 245 articles on cuprizone in the PubMed database. Others,for example,include areas of brain toxicity.
The research on the neurotoxic effects of hexachlorophne is much more extensive,especially with humans. I have covered it elsewhere in my website and in my blogs.
I think a Hexachlorophene Model would be an important addition to the use of cuprizone in "white matter" animal models of brain development and Psychiatric behavior.
Purvis (1991) showed that both Hexachlorophene and Cuprizone caused vacuoles (spaces) in the white matter of the rats. One important difference between Hexachlorophene and Cuprizone is that there is extensive research that hexachlorophene is a white matter neurotoxin in humans, especially babies. That should make hexachlorophene a focus of animal and human research.
Instead, as you will see, it is Cuprizone and its effect on the white matter of mice that has been the focus of extensive research. One area of research that is most interesting is the use of the Cuprizone behavior model for psychiatric research.
Particularly interesting is the use of Saraquel/Quetiapine as an effective treatment for the effects of cuprizone. Wouldn't this also be true with the effects of hexachlorophene on the vacuoles of the white matter of the human brain?
First, the direct comparison:
Hum Exp Toxicol. 1991 Nov;10(6):439-44.
A comparison of spongiosis induced in the brain by hexachlorophene, cuprizone and triethyl tin in the Sprague-Dawley rat.
Purves DC, Garrod IJ, Dayan AD.
DH Department of Toxicology, St Bartholomew's Hospital Medical College, London, UK.
The effect of hexachlorophene (HCP; 2,2'-methylenebis(3,4,6-trichlorophenol), cuprizone (CPZ; bicyclohexone oxaldihydrazone) and triethyl tin (TET; triethyl tin sulphate) in producing vacuoles in the brain of the Sprague-Dawley rat has been quantified by image analysis of the extent of the spongy change in the white matter.
Also,there was an interesting finding that cuprizone was more effective in causing vacuoles in mice than in rats. Hexachlorophene was far more efective than cuprizone in harming the white matter of rats. There were other aspects (eg tumors) of the research I have not noted here.
Cuprizone models
Here are some research examples of the use of Cuprizone as a human behavior model:
Behav Neurosci. 2009 Apr;123(2):418-29.
Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone.
Xu H, Yang HJ, Zhang Y, Clough R, Browning R, Li XM.
School of Medicine, Southern Illinois University Carbondale, Carbondale, IL 62901, USA. hxu@siumed.edu
C57BL/6 mice were given 0.2% cuprizone (CPZ) for 2 to 6 weeks while controls ate the same diet without CPZ. At various time points the animals were subjected to behavioral tests and their brains were analyzed...... inhibition, suggesting an increase in central nervous system activity and impaired sensorimotor gating. In addition, they showed lower activities of monoamine oxidase and dopamine beta hydroxylase in the hippocampus and prefrontal cortex, and had higher dopamine but lower norepinephrine levels in the prefrontal cortex. Mice exposed to CPZ for 4 to 6 weeks had less social interaction, which is an animal correlate of social withdrawal of patients with schizophrenia. Also, these CPZ-exposed mice showed evident brain demyelination, myelin break down, and loss of oligodendrocytes. At all time points the CPZ-exposed mice spent more time in the open arms of an elevated plus maze and exhibited spatial working memory impairment. These data are in line with evidence from human studies suggesting a putative role of white matter abnormality in the pathophysiology of schizophrenia. (c) 2009 APA, all rights reserved.
It is interesting to note that, like hexaclorophene, age of exposure seems important:
Prog Neuropsychopharmacol Biol Psychiatry. 2009 Aug 31;33(6):978-85. Epub 2009 May 14.
Demyelination in the juvenile period, but not in adulthood, leads to long-lasting cognitive impairment and deficient social interaction in mice.
Makinodan M, Yamauchi T, Tatsumi K, Okuda H, Takeda T, Kiuchi K, Sadamatsu M, Wanaka A, Kishimoto T.
Department of Psychiatry, Nara Medical University Faculty of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan. mmm@naramed-u.ac.jp
BACKGROUND: Dysmyelination is hypothesized to be one of the causes of schizophrenic symptoms. Supporting this hypothesis, demyelination induced by cuprizone was recently shown to cause schizophrenia-like symptoms in adult rodents [Xiao L, Xu H, Zhang Y, Wei Z, He J, Jiang W, et al. Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes. Mol Psychiatry 2008;13:697-708]. The present study asked if the timing of demyelination (i.e., juvenile period or adulthood) influenced abnormal behavior. METHODS: B57BL/6 mice were fed with 0.2% cuprizone either from postnatal day 29 (P29) to P56 (early demyelination group) or from P57 to P84 (late demyelination group).... the spatial working memory was impaired in both groups right after the cuprizone feeding ceased, consistent with previous studies, whereas only the early demyelination group exhibited impaired working memory after remyelination took place. In an open field test, social interactions were decreased in the early demyelination group, but not in the late group...CONCLUSIONS: Our findings suggest that the timing of demyelination has substantial impacts on behaviors of adult mice.
Most important for the Psychiatric model, the drug Serquel/Quetiapine seems to be an effective treatment for the cuprizone white matter neurotoxicity. here is one study:
Mol Psychiatry. 2008 Jul;13(7):697-708. Epub 2007 Aug 7.
Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes.
Xiao L, Xu H, Zhang Y, Wei Z, He J, Jiang W, Li X, Dyck LE, Devon RM, Deng Y, Li XM.
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada.
Recent neuroimaging and postmortem studies have reported abnormalities in white matter of schizophrenic brains, suggesting the involvement of oligodendrocytes in the etiopathology of schizophrenia. This view is being supported by gene microarray studies showing the downregulation of genes related to oligodendrocyte function and myelination in schizophrenic brain compared to control subjects. However, there is currently little information available on the response of oligodendrocytes to antipsychotic drugs (APDs), which could be invaluable for corroborating the oligodendrocyte hypothesis. In this study we found: (1) quetiapine (QUE, an atypical APD) treatment in conjunction with addition of growth factors increased the proliferation of neural progenitors isolated from the cerebral cortex of embryonic rats; (2) QUE directed the differentiation of neural progenitors to oligodendrocyte lineage through extracellular signal-related kinases; (3) addition of QUE increased the synthesis of myelin basic protein and facilitated myelination in rat embryonic cortical aggregate cultures; (4) chronic administration of QUE to C57BL/6 mice prevented cortical demyelination and concomitant spatial working memory impairment induced by cuprizone, a neurotoxin. These findings suggest a new neural mechanism of antipsychotic action of QUE, and help to establish a role for oligodendrocytes in the etiopathology and treatment of schizophrenia.
Here is a second study:
Schizophr Res. 2008 Dec;106(2-3):182-91. Epub 2008 Oct 19.
Quetiapine alleviates the cuprizone-induced white matter pathology in the brain of C57BL/6 mouse.
Zhang Y, Xu H, Jiang W, Xiao L, Yan B, He J, Wang Y, Bi X, Li X, Kong J, Li XM.
Department of Psychiatry, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
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.
These are a small sampling of the 245 articles on cuprizone in the PubMed database. Others,for example,include areas of brain toxicity.
The research on the neurotoxic effects of hexachlorophne is much more extensive,especially with humans. I have covered it elsewhere in my website and in my blogs.
I think a Hexachlorophene Model would be an important addition to the use of cuprizone in "white matter" animal models of brain development and Psychiatric behavior.
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