PET Evidence of the Effect of Donepezil on Cognitive Performance in an Animal Model of Chemobrain

Lim, Ilhan; Joung, Hye-Young; Yu, A Ram; Shim, Insop; Kim, Jin Su

doi:10.1155/2016/6945415

Cited by 39 publications

(28 citation statements)

References 30 publications

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“…This initial experiment aimed to study whether donepezil at a relatively high concentration could improve the cognition of normal zebrafish or not. This particular concentration was used based on several prior studies, especially in rats, which found the positive effects of donepezil in a similar concentration on rat cognitive performance [19][20][21][22][23]. As no adverse or beneficial effects on cognitive performance in zebrafish were observed, the adverse effect of donepezil was further examined in other tests.…”

Section: Preparation and Exposure To Donepezil Hclmentioning

confidence: 99%

Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments

et al. 2020

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Donepezil (DPZ) is an acetylcholinesterase inhibitor used for the clinical treatment of mild cognitive impairment. However, DPZ has been reported to have adverse effects, including causing abnormal cardiac rhythm, insomnia, vomiting, and muscle cramps. However, the existence of these effects in subjects without Dementia is unknown. In this study, we use zebrafish to conduct a deeper analysis of the potential adverse effects of DPZ on the short-term memory and behaviors of normal zebrafish by performing multiple behavioral and biochemical assays. Adult zebrafish were exposed to 1 ppm and 2.5 ppm of DPZ. From the results, DPZ caused a slight improvement in the short-term memory of zebrafish and induced significant elevation in aggressiveness, while the novel tank and shoaling tests revealed anxiolytic-like behavior to be caused by DPZ. Furthermore, zebrafish circadian locomotor activity displayed a higher reduction of locomotion and abnormal movement orientation in both low- and high-dose groups, compared to the control group. Biomarker assays revealed that these alterations were associated with an elevation of oxytocin and a reduction of cortisol levels in the brain. Moreover, the significant increases in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in muscle tissue suggest DPZ exposure induced muscle tissue oxidative stress and muscle weakness, which may underlie the locomotor activity impairment. In conclusion, we show, for the first time, that chronic waterborne exposure to DPZ can severely induce adverse effects on normal zebrafish in a dose-dependent manner. These unexpected adverse effects on behavioral alteration should be carefully addressed in future studies considering DPZ conducted on zebrafish or other animals.

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Section: Preparation and Exposure To Donepezil Hclmentioning

confidence: 99%

Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments

et al. 2020

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“…These drugs include the selective serotonin reuptake inhibitors (SSRIs) and the acetylcholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine), which have been approved to treat depression and AD, respectively. Donepezil alleviated cognitive problems in two studies of chemobrain (Winocur et al , ; Lim et al , ).…”

Section: Introductionmentioning

confidence: 99%

Cellular mechanisms and treatments for chemobrain: insight from aging and neurodegenerative diseases

2020

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Chemotherapy is a life-saving treatment for cancer patients, but also causes long-term cognitive impairment, or "chemobrain", in survivors. However, several challenges, including imprecise diagnosis criteria, multiple confounding factors, and unclear and heterogeneous molecular mechanisms, impede effective investigation of preventions and treatments for chemobrain. With the rapid increase in the number of cancer survivors, chemobrain is an urgent but unmet clinical need. Here, we leverage the extensive knowledge in various fields of neuroscience to gain insights into the mechanisms for chemobrain. We start by outlining why the post-mitotic adult brain is particularly vulnerable to chemotherapy. Next, through drawing comparisons with normal aging, Alzheimer's disease, and traumatic brain injury, we identify universal cellular mechanisms that may underlie the cognitive deficits in chemobrain. We further identify existing neurological drugs targeting these cellular mechanisms that can be repurposed as treatments for chemobrain, some of which were already shown to be effective in animal models. Finally, we briefly describe future steps to further advance our understanding of chemobrain and facilitate the development of effective preventions and treatments.Cognitive complaints are common among cancer patients during and after chemotherapy. Cross-sectional and longitudinal studies suggest that short-term memory, working memory, and verbal ability are most frequently affected, followed by visuospatial memory, executive functions, and attention span (for meta-analyses, see

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“…Using multiple dimensions in behavioral tasks may more reliably produce frontal cortex dysfunction in rodents (7, 8). Often, operant procedures are used to incorporate multiple dimensions of behavior, however, there are only a few examples in the chemobrain literature (3, 7).…”

Section: 0 Introductionmentioning

confidence: 99%

KU32 prevents 5-fluorouracil induced cognitive impairment

Sofis

Jarmolowicz

Kaplan

et al. 2017

Behavioural Brain Research

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Chemotherapy induced cognitive impairment (i.e. Chemobrain), involves acute and long-term deficits in memory, executive function, and processing speed. However, animal studies investigating these cognitive deficits have had mixed results. Chemotherapy treatment such as 5-Fluorouracil (5-FU) breaks down myelin integrity corresponding to hippocampal neurodegenerative deficits and mitochondrial dysfunction. There is little evidence, however, on pharmacological treatments that may target mitochondrial dysfunction. Using a differential reinforcement of low rates (DRL) task combining spatial and temporal components, the current study evaluated the preventative effects of the pharmacological agent KU32 on the behavior of rats treated with 5-FU (5-FU+Saline vs. 5FU+KU32). DRL performance was analyzed the day after the first set of injections (D1), the day after the second set of injections (D7) and the last day of the experiment (D14). The 5FU+KU32 group had earned significantly more reinforcers on the DRL task at D7 and D14 than the 5FU+Saline group. Further, the 5FU+KU32 group showed significantly better temporal discrimination. The 5FU+KU32 alone showed within-group improvement in temporal discrimination from D7 to D14. No significant differences were observed in spatial discrimination or amount of responding were observed between the groups or as a whole across treatment points. Future implications are discussed.

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PET Evidence of the Effect of Donepezil on Cognitive Performance in an Animal Model of Chemobrain

Cited by 39 publications

References 30 publications

Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments

Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments

Cellular mechanisms and treatments for chemobrain: insight from aging and neurodegenerative diseases

KU32 prevents 5-fluorouracil induced cognitive impairment

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