Nose-to-brain delivery of chrysin transfersomal and composite vesicles in doxorubicin-induced cognitive impairment in rats: Insights on formulation, oxidative stress and TLR4/NF-kB/NLRP3 pathways

Ibrahim, Shaimaa S.; Elseoud, Omar G. Abo; Mohamedy, Mohamed H.; Amer, Mohamed; Mohamed, Youssef Y.; Elmansy, Shehab A.; Kadry, Mohamed M.; Attia, A. A.; Fanous, Ragy A.; Kamel, Mahmoud S.; Solyman, Youssef A.; Shehata, Mazen S.; George, Mina Y.

doi:10.1016/j.neuropharm.2021.108738

Cited by 48 publications

(25 citation statements)

References 68 publications

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“…The spontaneous alternation y-maze tests multiple regions of the brain that contribute to working memory, including the prefrontal cortex, hippocampus, basal forebrain, dorsomedial thalamus, basal ganglia, and vestibular circuitry (Bizon et al, 2012 ; Kraeuter et al, 2019 ). Our results differ from prior studies demonstrating that doxorubicin-treated rats had a significantly lower percent of spontaneous alternations than control rats at 7, 9 or 10 days post-treatment (El-Derany and Noureldein, 2021 ; Ibrahim et al, 2021 ; Shaker et al, 2021 ). This difference may be a reflection of the later timing of neurocognitive testing in our study.…”

Section: Discussioncontrasting

confidence: 99%

Cancer treatment induces neuroinflammation and behavioral deficits in mice

Demos-Davies

Lawrence

Rogich

et al. 2023

Front. Behav. Neurosci.

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Introduction: Cancer survivors are increasingly diagnosed with a syndrome of neurocognitive dysfunction termed cancer-related cognitive impairment (CRCI). Chemotherapy and radiation therapy have been implicated in CRCI; however, its underlying pathogenesis remains unclear, hindering effective prevention or treatment.Methods: We used the hairless strain SKH1 (11–12-week-old) and treated the mice with radiation to the right hindlimb, doxorubicin (a chemotherapy agent), concurrent radiation, and doxorubicin, or no treatment (control). Neurocognition was evaluated via standardized behavioral testing following treatment. Mice were subsequently humanely euthanized, and plasma and brains were collected to identify inflammatory changes.Results: Mice treated with radiation, doxorubicin, or both radiation and doxorubicin demonstrated equivalent hippocampal dependent memory deficits and significant increases in activated microglia and astrocytes compared to control mice. Doxorubicin-treated mice had significantly increased plasma IL-6 and failed to gain weight compared to control mice over the study period.Discussion: This study demonstrates that non-brain directed radiation induces both gliosis and neurocognitive deficits. Moreover, this work presents the first characterization of SKH1 mice as a relevant and facile animal model of CRCI. This study provides a platform from which to build further studies to identify potential key targets that contribute to CRCI such that strategies can be developed to mitigate unintended neuropathologic consequences associated with anticancer treatment.

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Section: Discussioncontrasting

confidence: 99%

Cancer treatment induces neuroinflammation and behavioral deficits in mice

Demos-Davies

Lawrence

Rogich

et al. 2023

Front. Behav. Neurosci.

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“…We believe this is the first study documenting the roles of the NLRP3 inflammasome in cisplatin-induced cognitive impairment. These data, together with previous findings with doxorubicin (23), suggest NLRP3-driven inflammatory pathways are strongly implicated in cognitive changes following chemotherapy. Coadministration of cisplatin with FTY720 attenuates MnSOD nitration and inactivation and NLRP3 activation (Figure 2, A-D).…”

Section: Resultssupporting

confidence: 83%

“…Peroxynitrite nitrates mitochondrial manganese superoxide dismutase (MnSOD) at Tyr-34 via an Mn-catalyzed process that inactivates the enzyme by more than 80% and results in mitochondrial dysfunction (20,21). In contrast, NLRP3 is critical for formation of interleukin 1β (IL-1β) and IL-18, inflammatory cytokines with known roles in cognitive impairment (22,23). As mitochondrial dysfunction and neuroinflammation in the CNS are 2 drosphingosine, nor in sphingomyelin or glycosylceramides (Supplemental Figures 2 and 3).…”

Section: Resultsmentioning

confidence: 99%

Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment

Squillace¹,

Niehoff²,

Doyle³

et al. 2022

Journal of Clinical Investigation

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“…It was reported that TLR4 activation in the hippocampus and prefrontal cortex is the linchpin in cisplatin-induced NLRP3 inflammasome activation and increased IL-1β formation leading to cognitive impairment in mice (S. Squillace et al, unpublished). Similar results were obtained with doxorubicin, another widely used chemotherapeutic [96]. Because compelling evidence suggests that the microbiota-gut-brain axis is also involved in CICI [97][98][99], it is important to investigate whether dysregulation of TLR signaling in enteric glia anticipates CNS neurodegeneration (see Outstanding questions).…”

Section: Concluding Remarks and Future Perspectivessupporting

confidence: 55%