A novel flavanone derivative ameliorates cuprizone-induced behavioral changes and white matter pathology in the brain of mice

Sun, Zhengyu; Gu, Hong-Shun; Chen, Xi; Zhang, Lan; Li, Xinmin; Zhang, Jianwei; Li, Lin

doi:10.1016/j.psychres.2017.07.075

Cited by 12 publications

(7 citation statements)

References 53 publications

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“…Thus, the purpose of this research is to explore venlafaxine effect on cognitive and depression-like processes with respect to demyelination and inflammatory processes in the brain. The CPZ-induced demyelination mouse model was utilized to investigate cognitive impairments and mood symptoms associated with OL cell death and acute demyelination and associated neuroinflammation (Sun et al., 2017). Y-maze testing evaluated the cognitive effects of venlafaxine on CPZ-induced demyelination; a series of FST and TST behavioral tests assessed depression-like behaviors.…”

Section: Discussionmentioning

confidence: 99%

Venlafaxine Improves the Cognitive Impairment and Depression-Like Behaviors in a Cuprizone Mouse Model by Alleviating Demyelination and Neuroinflammation in the Brain

Zhang

Adebiyi

et al. 2019

Front. Pharmacol.

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Growing evidence has implicated that myelin deficits and neuroinflammation are the coexisted pathological features that contribute to the mood swing and cognitive decline in major depressive disorder (MDD) and multiple sclerosis (MS). Therefore, attenuation of neuroinflammation and reduction of demyelination became newly emerging treatment strategies for the mood and cognitive symptoms. Antidepressant venlafaxine has been used in depression and anxiety through its multiple neuroprotective effects. However, it is unclear whether venlafaxine can improve myelin integrity and alter inflammation status in the brain. By using a well-established cuprizone-induced acute mouse model of demyelination, we investigated the protective effects of venlafaxine on these facets. The cuprizone-fed animals exhibited cognitive impairment and mood disturbances together with myelin loss and prominent neuroinflammation in the brain. Our present study showed that a high dose of venlafaxine alleviated the loss of myelin and oligodendrocytes (OLs), mitigated depression-like behaviors, and improved cognitive function in cuprizone-fed animals. Data from the present study also showed that venlafaxine reduced microglia-mediated inflammation in the brains of cuprizone-fed animals. These findings suggest that venlafaxine may exert its therapeutic effects via facilitating myelin integrity and controlling neuroinflammation, which may provide extra benefits to MS patients with depression and anxiety beyond the symptom management.

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Section: Discussionmentioning

confidence: 99%

Venlafaxine Improves the Cognitive Impairment and Depression-Like Behaviors in a Cuprizone Mouse Model by Alleviating Demyelination and Neuroinflammation in the Brain

Zhang

Adebiyi

et al. 2019

Front. Pharmacol.

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“…Observations that were compatible with this notion included impaired spatial working memory in the Y‐maze test, decreased paired‐pulse inhibition and lower intensity of social interactions observed in mice that received 0.2% to 0.4% cuprizone in the diet for short periods 59,60,67,70 . Furthermore, the sensitivity of these phenotypes to antipsychotic drugs such as quetiapine or clozapine, 52,54,55,66,70,71 as well as increased levels of brain dopamine in cuprizone‐treated mice 57,60,70 also supported this view. Our touchscreen‐based tests showed several additional behavioural changes that further extend the range of putative schizophrenia‐related symptoms in cuprizone‐treated mice.…”

Section: Discussionmentioning

confidence: 76%

“…In our experiments, we showed multiple alterations of spontaneous behaviour and learning parameters in mice treated with cuprizone. One of the characteristic behavioural changes in the cuprizone model of MS is hyperactive locomotion reflected in more frequent crosses of infrared beams, total distances travelled, and higher speeds in the open field, 50‐56 or in the total number of Y‐maze arm entrances 57‐59 . Nonetheless, in other studies, no clear hyperactivity in the open field was seen, 60‐64 and one study reported reduced total distance travelled in mice that received cuprizone with chow for 5 weeks 65 .…”

Section: Discussionmentioning

confidence: 99%

Cognitive disturbances in the cuprizone model of multiple sclerosis

Kopanitsa

Lehtimäki²,

Forsman³

et al. 2020

Genes Brain and Behavior

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Cognitive problems frequently accompany neurological manifestations of multiple sclerosis (MS). However, during screening of preclinical candidates, assessments of behaviour in mouse models of MS typically focus on locomotor activity. In the present study, we analysed cognitive behaviour of 9 to 10‐week‐old female C57Bl/6J mice orally administered with the toxin cuprizone that induces demyelination, a characteristic feature of MS. Animals received 400 mg/kg cuprizone daily for 2 or 4 weeks, and their performance was compared with that of vehicle‐treated mice. Cuprizone‐treated animals showed multiple deficits in short touchscreen‐based operant tasks: they responded more slowly to visual stimuli, rewards and made more errors in a simple rule‐learning task. In contextual/cued fear conditioning experiments, cuprizone‐treated mice showed significantly lower levels of contextual freezing than vehicle‐treated mice. Diffusion tensor imaging showed treatment‐dependent changes in fractional anisotropy as well as in axial and mean diffusivities in different white matter areas. Lower values of fractional anisotropy and axial diffusivity in cuprizone‐treated mice indicated developing demyelination and/or axonal damage. Several diffusion tensor imaging measurements correlated with learning parameters. Our results show that translational touchscreen operant tests and fear conditioning paradigms can reliably detect cognitive consequences of cuprizone treatment. The suggested experimental approach enables screening novel MS drug candidates in longitudinal experiments for their ability to improve pathological changes in brain structure and reverse cognitive deficits.

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“…The beneficial effects of our treatments on WM inflammation in TGF HCD mice are supported by previous reports of improved WM integrity following EX training programs (84) or SV treatment (12, 85), which seems to relate to preserved cognitive abilities. It is also interesting to note that mice initially fed a cuprizone diet that causes demyelination, recover cognitive abilities when taken off the diet (86), which may be attributable to a shift in the role of Gal-3 during remyelination (79).…”

Section: Discussionmentioning

confidence: 99%

Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia

et al. 2019

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Aerobic physical exercise (EX) and controlling cardiovascular risk factors in midlife can improve and protect cognitive function in healthy individuals and are considered to be effective at reducing late-onset dementia incidence. By investigating commonalities between these preventative approaches, we sought to identify possible targets for effective interventions. We compared the efficacy of EX and simvastatin (SV) pharmacotherapy to counteract cognitive deficits induced by a high-cholesterol diet (2%, HCD) in mice overexpressing TGF-β1 (TGF mice), a model of vascular cognitive impairment and dementia. Cognitive deficits were found in hypercholesterolemic mice for object recognition memory, and both SV and EX prevented this decline. EX improved stimulus-evoked cerebral blood flow responses and was as effective as SV in normalizing endothelium-dependent vasodilatory responses in cerebral arteries. The up-regulation of galectin-3–positive microglial cells in white matter (WM) of HCD-fed TGF mice with cognitive deficits was significantly reduced by both SV and EX concurrently with cognitive recovery. Altered hippocampal neurogenesis, gray matter astrogliosis, or microgliosis did not correlate with cognitive deficits or benefits. Overall, results indicate that SV and EX prevented cognitive decline in hypercholesterolemic mice and that they share common sites of action in preventing endothelial cell dysfunction and reducing WM inflammation.—Trigiani, L. J., Royea, J., Tong, X.-K., Hamel, E. Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia.

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A novel flavanone derivative ameliorates cuprizone-induced behavioral changes and white matter pathology in the brain of mice

Cited by 12 publications

References 53 publications

Venlafaxine Improves the Cognitive Impairment and Depression-Like Behaviors in a Cuprizone Mouse Model by Alleviating Demyelination and Neuroinflammation in the Brain

Venlafaxine Improves the Cognitive Impairment and Depression-Like Behaviors in a Cuprizone Mouse Model by Alleviating Demyelination and Neuroinflammation in the Brain

Cognitive disturbances in the cuprizone model of multiple sclerosis

Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia

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