KU32 prevents 5-fluorouracil induced cognitive impairment

Sofis, Michael J.; Jarmolowicz, David P.; Kaplan, Sam V.; Gehringer, Rachel C.; Lemley, Shea M.; Garg, Gaurav; Blagg, Brian S. J.; Johnson, Michael A.

doi:10.1016/j.bbr.2017.03.042

Cited by 16 publications

(9 citation statements)

References 27 publications

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“…Neuronal integrity and cognitive function are eventually impaired [17]. Antitumor drug 5-fluorouracil (5-Fu) can decompose myelin sheath integrity and is associated with hippocampal neurodegenerative defects and mitochondrial dysfunction [18]. Rodents exposed to cyclophosphamide or doxorubicin for long periods of time show impairments in spatial memory and episodic memory, with disruption of hippocampal neurogenesis [19].…”

Section: Direct Neurotoxic Effects Of Chemotherapy Drugsmentioning

confidence: 99%

Pathogenesis, Assessments, and Management of Chemotherapy-Related Cognitive Impairment (CRCI): An Updated Literature Review

Mao

Dong

et al. 2020

Journal of Oncology

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There are various cancer treatments at present, and chemotherapy is one of the main methods. Chemotherapy-related cognitive impairment (CRCI), as one of the side effects of chemotherapy, has gradually attracted the attention of more and more researchers. CRCI has been verified by subjective reports and objective neuropsychological tests so far. But oncologists’ understanding of it and its treatments are still incomplete. In this review, we mainly give a comprehensive overview of the mechanism of CRCI, then describe a variety of evaluation methods, and finally summarize the treatment approaches under current medical conditions and compare it with an excellent article published in 2015 with the aim of providing directions for future research and better understanding of CRCI for clinicians.

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Section: Direct Neurotoxic Effects Of Chemotherapy Drugsmentioning

confidence: 99%

Pathogenesis, Assessments, and Management of Chemotherapy-Related Cognitive Impairment (CRCI): An Updated Literature Review

Mao

Dong

et al. 2020

Journal of Oncology

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“…Various therapeutic approaches have been attempted for chemobrain. A 5-fluorouracil- induced cognitive impairment in rats has been prevented with KU-32: a small molecule, C-terminal inhibitor of the molecular chaperone of heat shock protein 90 [43]. Therapeutic mechanism of Ku-32 is likely through electrophysiological and bioenergetic neuroprotection [44].…”

Section: Chemobrainmentioning

confidence: 99%

Chemobrain as a Product of Growing Success in Chemotherapy - Focus On Glia As Both A Victim And A Cure

Walczak¹,

Janowski²

2019

Neuropsychiatry

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Chemotherapy-induced cognitive impairment or chemobrain is a frequent consequence of cancer treatment with many psychiatric features. Ironically, the increasing efficacy of chemotherapy leaves growing number of patients alive with chemobrain. Therefore, there is an urgent need for strategies capable of returning cancer survivors back to their pre-morbid quality of life. Molecular mechanisms of chemobrain are largely unknown. Over the last decade there was a lot of emphasis in preclinical research on inflammatory consequences of chemotherapy and oxidative stress but so far none of these approaches were translated into clinical scenario. The co-administration of chemotherapy with protective agents was evaluated preclinically but it should be introduced with caution as potential interference was not yet studied and that could blunt therapeutic efficacy. Stem cell-based regenerative medicine approach has so far been exploited very sparsely in the context of chemobrain and the focus was on indirect mechanisms or neuronal replacement in the hippocampus. However, there is evidence for widespread white matter abnormalities in patients with chemobrain. This is quite logical considering life-long proliferation and turnover of glial cells, which makes them vulnerable to chemotherapeutic agents. Feasibility of glia replacement has been established in mice with global dysmyelination where profound therapeutic effect has been observed but only in case of global cell engraftment (across the entire brain). While global glia replacement has been achieved in mice translation to clinical setting might be challenging due to much larger brain size. Therefore, a lot of attention should be directed towards the route of administration to accomplish widespread cell delivery. Techniques facilitating that broad cell distribution including intra-arterial and intrathecal methods should be considered as very compelling options. Summarizing, chemobrain is a rapidly growing medical problem and global glia replacement should be considered as worthwhile therapeutic strategy.

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“…Unfortunately, 5‐FU causes chemobrain and cognitive impairment as a major adverse event 114 . Studies in rats revealed that 5‐FU treatment along with KU‐32 produced significant neuroprotection against 5‐FU‐induced cognitive impairment 115 …”

Section: Diabetic Peripheral Neuropathymentioning

confidence: 99%

The role and therapeutic potential of Hsp90, Hsp70, and smaller heat shock proteins in peripheral and central neuropathies

Chaudhury

Keegan

Blagg

2020

Medicinal Research Reviews

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Heat shock proteins (Hsps) are molecular chaperones that also play important roles in the activation of the heat shock response (HSR). The HSR is an evolutionary conserved and protective mechanism that is used to counter abnormal physiological conditions, stressors, and disease states, such as those exemplified in cancer and/or neurodegeneration. In normal cells, heat shock factor‐1 (HSF‐1), the transcription factor that regulates the HSR, remains in a dormant multiprotein complex that is formed upon association with chaperones (Hsp90, Hsp70, etc.), co‐chaperones, and client proteins. However, under cellular stress, HSF‐1 dissociates from Hsp90 and induces the transcriptional upregulation of Hsp70 to afford protection against the encountered cellular stress. As a consequence of both peripheral and central neuropathies, cellular stress occurs and results in the accumulation of unfolded and/or misfolded proteins, which can be counterbalanced by activation of the HSR. Since Hsp90 is the primary regulator of the HSR, modulation of Hsp90 by small molecules represents an attractive therapeutic approach against both peripheral and central neuropathies.

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KU32 prevents 5-fluorouracil induced cognitive impairment

Cited by 16 publications

References 27 publications

Pathogenesis, Assessments, and Management of Chemotherapy-Related Cognitive Impairment (CRCI): An Updated Literature Review

Pathogenesis, Assessments, and Management of Chemotherapy-Related Cognitive Impairment (CRCI): An Updated Literature Review

Chemobrain as a Product of Growing Success in Chemotherapy - Focus On Glia As Both A Victim And A Cure

The role and therapeutic potential of Hsp90, Hsp70, and smaller heat shock proteins in peripheral and central neuropathies

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