Doxorubicin (DOX) is the most widely used broad-spectrum anticancer agent, either alone or in combination, for most cancers including breast cancer. Long-term use of chemotherapeutic agents to treat breast cancer patients results in cognitive complications with a negative impact on survivors’ quality of life. The study objective was to evaluate rutin (RUT) for its neuroprotective effect against DOX in human neuroblastoma (IMR32) cells in vitro and study its potential to ameliorate DOX-induced cognitive dysfunction in Wistar rats. Cell viability assay (3-[4,5 dimethyl thiazol-2-yl]-2,5-diphenyl tetrazolium bromide), neurite growth assay, detection of apoptosis by (acridine orange/ethidium bromide) staining, intracellular reactive oxygen species (ROS) assay, and flowcytometric analysis were carried out to assess neuroprotective potential against DOX. An in vivo study was conducted for assessing protective effect of RUT against memory deficit associated with DOX-induced chemobrain using object recognition task (ORT). Locomotion was assessed using open field test. Serum biochemistry, acetylcholinesterase, oxidative stress markers in hippocampus, and frontal cortex were assessed. Histopathological analysis of major organ systems was also carried out. Prior exposure to RUT at 100 µM protected IMR32 cells from DOX (1 µM) neurotoxicity. DOX exposure resulted in increased cellular death, apoptosis, and intracellular ROS generation with inhibition of neurite growth in differentiated IMR32 cells, which was significantly ameliorated by RUT. Cognitive dysfunction was induced in Wistar rats by administering ten cycles of DOX (2.5 mg/kg, intra-peritoneal, once in 5 days), as we observed significant impairment of episodic memory in ORT. Coadministration with RUT (50 mg/kg, per os) significantly prevented memory deficits in vivo without any confounding influence on locomotor activity. RUT also offered protection against DOX-induced myelosuppression, cardiotoxicity, and nephrotoxicity. In conclusion, RUT may be a possible adjuvant therapeutic intervention to alleviate cognitive and other complications associated with DOX chemotherapy.
Cognitive dysfunction by chemotherapy compromises the quality of life in cancer patients. Tea polyphenols are known chemopreventive agents. The present study was designed to evaluate the neuroprotective potential of (+) catechin hydrate (catechin), a tea polyphenol, in IMR-32 neuroblastoma cells in vitro and alleviation of episodic memory deficit in Wistar rats in vivo against a widely used chemotherapeutic agent, Doxorubicin (DOX). In vitro, neuroprotective studies were assessed in undifferentiated IMR-32 cells using percentage viability and in differentiated cells by neurite length. These studies showed catechin increased percentage viability of undifferentiated IMR-32 cells. Catechin pretreatment also showed an increase in neurite length of differentiated cells. In vivo neuroprotection of catechin was evaluated using novel object recognition task in time-induced memory deficit model at 50, 100 and 200 mg/kg dose and DOX-induced memory deficit models at 100 mg/kg dose. The latter model was developed by injection of DOX (2.5 mg/kg, i.p.) in 10 cycles over 50 days in Wistar rats. Catechin showed a significant reversal of time-induced memory deficit in a dose-dependent manner and prevention of DOX-induced memory deficit at 100 mg/kg. In addition, catechin treatment showed a significant decrease in oxidative stress, acetylcholine esterase and neuroinflammation in the hippocampus and cerebral cortex in DOX-induced toxicity model. Hence, catechin may be a potential adjuvant therapy for the amelioration of DOX-induced cognitive impairment which may improve the quality of life of cancer survivors. This improvement might be due to the elevation of antioxidant defense, prevention of neuroinflammation and inhibition of acetylcholine esterase enzyme.
Sesame (Sesamum indicum L.) seeds have been authenticated for its medicinal value in both Chinese and Indian systems of medicine. Its numerous potential nutritional benefits are attributed to its main bioactive constituents, sesamol. As a result of those studies, several molecular mechanisms are emerging describing the pleiotropic biological effects of sesamol. This review summarized the most interesting in vitro and in vivo studies on the biological effects of sesamol. The present work summarises data available from Pubmed and Scopus database. Several molecular mechanisms have been elucidated describing the pleiotropic biological effects of sesamol. Its major therapeutic effects have been elicited in managing oxidative and inflammatory conditions, metabolic syndrome and mood disorders. Further, compelling evidence reflected the ability of sesamol in inhibiting proliferation of the inflammatory cell, prevention of invasion and angiogenesis via affecting multiple molecular targets and downstream mechanisms. Sesamol is a safe, non‐toxic chemical that mediates anti‐inflammatory effects by down‐regulating the transcription of inflammatory markers such as cytokines, redox status, protein kinases, and enzymes that promote inflammation. In addition, sesamol also induces apoptosis in cancer cells via mitochondrial and receptor‐mediated pathways, as well as activation of caspase cascades. In the present review, several pharmacological effects of sesamol are summarised namely, antioxidant, anti-cancer, neuroprotective, cardioprotective, anti-inflammatory, hypolipidemic, radioprotective, anti-aging, anti-ulcer, anti-dementia, anti-depressant, antiplatelet, anticonvulsant, anti-anxiolytic, wound healing, cosmetic (skin whitening), anti-microbial, matrix metalloproteinase (MMPs) inhibition, hepatoprotective activity and other biological effects. Here we have summarized the proposed mechanism behind these pharmacological effects.
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