Ondansetron attenuates cisplatin-induced behavioral and cognitive impairment through downregulation of NOD-like receptor inflammasome pathway.

Cisplatin is an effective and commonly used chemotherapeutic drug; however, its use is accompanied by several adverse effects, including chemobrain. Ondansetron is a 5-HT3 antagonist, commonly used in prophylactic against chemotherapy-induced nausea and vomiting. Moreover, it has been identified as a novel neuroprotective agent in different animal models. However, its protective role against chemotherapy-induced chemobrain has not been investigated. The current study was the first study that explored the potential neuroprotective effect of ondansetron against cisplatin-induced chemobrain in rats. Cisplatin (5 mg/Kg) was injected intraperitoneally, once weekly, for 4 weeks with the daily administration of ondansetron (0.5 and 1 mg/Kg). Compared to the cisplatin-treated group, ondansetron administration showed a significant decrease in the latency time and a significant increase in ambulation, rearing, and grooming frequency in the open field test (OFT). Moreover, a significant improvement in the latency time in the rotarod and passive avoidance tests, following ondansetron administration. In addition, ondansetron treatment increased the percentage of alternation in the Y-maze test. Also, ondansetron showed a remarkable enhancement in the biochemical parameters in the hippocampus. It increased the acetylcholine (Ach) level and decreased the level of the acetylcholine esterase enzyme (AchE). Ondansetron significantly decreased interleukin-1ß (Il-1ß), tumor necrosis factor-alpha (TNF-α), toll-like receptor-4 (TLR-4), NOD-like receptor-3 (NLRP3) inflammasome as well as caspase-1 and caspase-3 levels. Furthermore, ondansetron significantly decreased the levels of copper transporter-1(CTR1) expression in the hippocampus. Collectively, these findings suggest that ondansetron may exhibit a neuroprotective and therapeutic activity against cisplatin-induced chemobrain.

The effectiveness of anti-inflammatory agents in reducing chemotherapy-induced cognitive impairment in preclinical models - A systematic review.

Chemotherapy-induced cognitive impairment (CICI) is a debilitating condition resulting from chemotherapy administration for cancer treatment. CICI is characterised by various cognitive impairments, including issues with learning, memory, and concentration, impacting quality of life. Several neural mechanisms are proposed to drive CICI, including inflammation, therefore, anti-inflammatory agents could ameliorate such impairments. Research is still in the preclinical stage; however, the efficacy of anti-inflammatories to reduce CICI in animal models is unknown. Therefore, a systematic review was conducted, with searches performed in PubMed, Scopus, Embase, PsycInfo and Cochrane Library. A total of 64 studies were included, and of the 50 agents identified, 41 (82%) reduced CICI. Interestingly, while non-traditional anti-inflammatory agents and natural compounds reduced impairment, the traditional agents were unsuccessful. Such results must be taken with caution due to the heterogeneity observed in terms of methods employed. Nevertheless, preliminary evidence suggests anti-inflammatory agents could be beneficial for treating CICI, although it may be critical to think beyond the use of traditional anti-inflammatories when considering which specific compounds to prioritise in development.

Piperine loaded metal organic frameworks reverse doxorubicin induced chemobrain in adult zebrafish.

The study's primary goal was to enhance medicinal potential of piperine (PIP)-loaded zeolitic imidazolate frameworks-8 (PIP@ZIF-8) against doxorubicin (DOX)-induced cognitive impairments in zebrafish. Herein, PIP@ZIF-8 was synthesized via easy, economical and reproducible ultrasonication method followed by spray drying technology. ZIF-8's structural integrity has been confirmed by PXRD, and even after PIP was encapsulated, the structure of ZIF-8 remained unchanged. Pure ZIF-8 and PIP@ZIF-8 were subjected to TEM analysis, which revealed hexagonal morphology with a nanosize range. FTIR and UV-Visible spectroscopy studies confirmed the drug loading of ZIF-8. Studies on in vitro release revealed 71.48 ± 7.21% and 34.56 ± 5.35% PIP release from PIP@ZIF-8 and unformulated PIP, respectively in pH 7.4. The highest antioxidant scavenging results were obtained with vitamin C (73.77 ± 6.7%) at an intensity of 200 µg/ml, though it was 65.09 ± 2.5% and 57.99 ± 3.1% for PIP@ZIF-8 and PIP, respectively. In vivo studies on zebrafish showed that DOX administration remarkably impaired cognitive activity in T-Maze, and downregulated spatial memory and locomotor activity in the open field test. In addition, DOX administration caused a downregulation in GSH and SOD levels and increase in LPO, AChE and TNF-α levels compared to the vehicle group along with changes in brain histopathology. Further, PIP@ZIF-8 reversed the DOX-induced cognitive impairments by its antioxidant and neuroprotective properties. It can be concluded that PIP@ZIF-8 has a promising therapeutic potential against the chemotherapy-induced cognitive impairments in zebrafish.

Inhibition of NLRP3 alleviated chemotherapy-induced cognitive impairment in rats.

Chemotherapy results in long-term effects on cognitive dysfunction called chemotherapy-induced cognitive impairment (CICI) in cancer survivors. However, little is known about the potential molecular mechanisms of CICI. This study aimed to determine the role and potential underlying mechanisms of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in cognitive impairments induced by chemotherapeutic agents commonly used in breast cancer. The cognitive effects of chemotherapy were investigated in a rat model using the cocktail of doxorubicin and cyclophosphamide. The NLRP3 pathway was found to be differentially expressed after chemotherapy by iTRAQ-based proteomic analysis of normal and chemotherapeutic hippocampi. Treatment with the NLRP3 inhibitor MCC950 following chemotherapy significantly reduced cognitive impairment and decreased the expression of NLRP3, caspase-1 and ASC. Chemotherapy led to increased expression of the glial response markers Iba-1 and GFAP and the axonal injury markers NF-L and NF-M, an elevated number of apoptotic cells and enhanced microstructural damage to axons and mitochondria, while MCC950 treatment alleviated the glial response, cell death and axonal injury. The protective effect of MCC950 was related to the NLRP3 pathway and levels of inflammatory cytokines (TNF-α, IL-1ß, IL-18, IL-6, IL-4, and IL-10) and oxidative stress-responsive markers (SOD, MDA, CAT and GSH). The results indicate that CICI is associated with NLRP3 pathway-induced oxidative damage and the inflammatory response and provide a potential therapeutic target to treat cognitive impairment after chemotherapy (doxorubicin and cyclophosphamide).

Modulation of mitochondrial dynamics rescues cognitive function in rats with 'doxorubicin-induced chemobrain' via mitigation of mitochondrial dysfunction and neuroinflammation.

Doxorubicin (DOX), an effective, extensively used chemotherapeutic drug, can cause cognitive deterioration in cancer patients. The associated debilitating neurological sequelae are referred to as chemobrain. Our recent work demonstrated that Dox treatment resulted in an imbalance in mitochondrial dynamics, ultimately culminating in cognitive decline in rats. Therefore, in this study, we aim to explore the therapeutic efficacy of a pharmacological intervention, which modulates mitochondrial dynamics using a potent mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promoter (M1) against Dox-induced chemobrain. In the study, male Wistar rats were randomly assigned to receive either normal saline solution or six doses of Dox (3 mg·kg-1 ) via intraperitoneal injection. Then, the Dox-treated rats were intraperitoneally given either 1% DMSO as the vehicle, Mdivi-1 (1.2 mg·kg-1 ), M1 (2 mg·kg-1 ), or a combined treatment of Mdivi-1 and M1 for 30 consecutive days. Long-term learning and memory were evaluated using the novel object location task and novel object recognition task. Following euthanasia, the rat brains were dissected to enable further molecular investigation. We demonstrated that long-term treatment with mitochondrial dynamic modulators suppressed mitochondrial fission in the hippocampus following Dox treatment, leading to an improvement in brain homeostasis. Mitochondrial dynamic modulator treatments restored cognitive function in Dox-treated rats by attenuating neuroinflammation, decreasing oxidative stress, preserving synaptic integrity, reducing potential Alzheimer's related lesions, and mitigating both apoptosis and necroptosis following Dox administration. Together, our findings suggested that mitochondrial dynamics modulators protected against Dox-induced cognitive impairment by rebalancing mitochondrial homeostasis and attenuating both oxidative and inflammatory insults.

Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment.

Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient's quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity.

Targeting the A3 adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice.

Cisplatin is used to combat solid tumors. However, patients treated with cisplatin often develop cognitive impairments, sensorimotor deficits, and peripheral neuropathy. There is no FDA-approved treatment for these neurotoxicities. We investigated the capacity of a highly selective A3 adenosine receptor (AR) subtype (A3AR) agonist, MRS5980, to prevent and reverse cisplatin-induced neurotoxicities. MRS5980 prevented cisplatin-induced cognitive impairment (decreased executive function and impaired spatial and working memory), sensorimotor deficits, and neuropathic pain (mechanical allodynia and spontaneous pain) in both sexes. At the structural level, MRS5980 prevented the cisplatin-induced reduction in markers of synaptic integrity. In-situ hybridization detected Adora3 mRNA in neurons, microglia, astrocytes and oligodendrocytes. RNAseq analysis identified 164 genes, including genes related to mitochondrial function, of which expression was changed by cisplatin and normalized by MRS5980. Consistently, MRS5980 prevented cisplatin-induced mitochondrial dysfunction and decreased signs of oxidative stress. Transcriptomic analysis showed that the A3AR agonist upregulates genes related to repair pathways including NOTCH1 signaling and chromatin modification in the cortex of cisplatin-treated mice. Importantly, A3AR agonist administration after completion of cisplatin treatment resolved cognitive impairment, neuropathy and sensorimotor deficits. Our results highlight the efficacy of a selective A3AR agonist to prevent and reverse cisplatin-induced neurotoxicities via preventing brain mitochondrial damage and activating repair pathways. An A3AR agonist is already in cancer, clinical trials and our results demonstrate management of neurotoxic side effects of chemotherapy as an additional therapeutic benefit.

The diuretic amiloride attenuates doxorubicin-induced chemobrain in rats: Behavioral and mechanistic study.

Cognitive impairment or "chemobrain" is a troublesome adverse effect which had been increasingly reported by cancer patients after doxorubicin (DOX) chemotherapy. Notably, Hypertension, a very common comorbidity in cancer patients, could pose a greater risk for negative cognitive outcomes. Amiloride (AML) is an antihypertensive, potassium-sparing diuretic that has been proven to be neuroprotective in different experimental models; this can be attributed to its ability to inhibit different ion transporters such as Na+/H+ exchanger (NHE), which upon excessive activation can result in intracellular cationic overload, followed by oxidative damage and cellular death. Accordingly, this study was designed to investigate the potential neuroprotective effect of AML against DOX-induced chemobrain and to elucidate possible underlying mechanisms. Briefly, Histopathological examination and neurobehavioral testing (Morris water maze, Y maze and passive avoidance test) showed that AML co-treatment (10 mg/kg/day) markedly attenuated DOX (2 mg/kg/week)-induced neurodegeneration and memory impairment after 4 weeks of treatments. We found that DOX administration up-regulated NHE expression and increased lactic acid content in the hippocampus which were markedly opposed by AML. Moreover, AML mitigated DOX-induced neuroinflammation and decreased hippocampal tumor necrosis factor-α level, nuclear factor kappa-B, and cyclooxygenase-2 expression. Additionally, AML counteracted DOX-induced hippocampal oxidative stress as indicated by normalized malondialdehyde and glutathione levels. Furthermore, AML halted DOX-induced hippocampal apoptosis as evidenced by decreased caspase-3 activity and lower cytochrome c immunoexpression. Our results in addition to the previously reported antitumor effects of AML and its ability to mitigate cancer resistance to DOX therapy could point toward possible new repositioning scenarios of the diuretic AML especially regarding hypertensive cancer patients.

Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial.

BACKGROUND: Chemotherapy-related cognitive impairment (CRCI) is highly prevalent in patients with cancer and is associated with poor outcomes and quality of life. To date, the management of CRCI remains a clinical challenge. Herein, we aim to determine the preventive effects of probiotics on CRCI development and underlying mechanisms. METHODS: We conducted a randomised, double-blind and placebo-controlled trial (ChiCTR-INQ-17014181) of 159 patients with breast cancer and further investigated the underlying mechanism in a pre-clinical setting. From 2018 to 2019, patients with breast cancer (Stage I-III) who needed adjuvant chemotherapy were screened, enrolled and randomly assigned to receive either probiotics or placebo (three capsules, twice/day) during chemotherapy. Their cognition, anxiety and depression were assessed with well-established assays; their plasma biomarkers, metabolites and faecal microbiota compositions were measured. In addition, the systemic effects of the metabolites found in the clinical trial on long-term potentiation, synapse injury, oxidative stress and glial activation were assessed in rats. RESULTS: Probiotics supplement significantly decreased the incidence of CRCI, improved the allover cognitive functions, changed the gut microbial composition and modulated nine plasma metabolite changes. Among these metabolites, p-Mentha-1,8-dien-7-ol, Linoelaidyl carnitine and 1-aminocyclopropane-1-carboxylic acid were negatively correlated with the occurrence of CRCI. Furthermore, probiotics supplement increased plasma p-Mentha-1,8-dien-7-ol in rats. Administration of exogenous p-Mentha-1,8-dien-7-ol significantly alleviated chemotherapy-induced long-term potentiation impairment, synapse injury, oxidative stress and glial activation in the hippocampus of rats. CONCLUSION: Our data indicated that probiotics supplement prevents the occurrence of CRCI in patients with breast cancer via modulating plasma metabolites, including p-Mentha-1,8-dien-7-ol. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-INQ-17014181) [http://www.chictr.org.cn/showproj.aspx?proj=24294].

Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions.

A wide range of cognitive deficits, including memory loss associated with hippocampal dysfunction, have been widely reported in cancer survivors who received chemotherapy. Changes in both white matter and gray matter volume have been observed following chemotherapy treatment, with reduced volume in the medial temporal lobe thought to be due in part to reductions in hippocampal neurogenesis. Pre-clinical rodent models confirm that common chemotherapeutic agents used to treat various forms of non-CNS cancers reduce rates of hippocampal neurogenesis and impair performance on hippocampally-mediated learning and memory tasks. We review the pre-clinical rodent literature to identify how various chemotherapeutic drugs affect hippocampal neurogenesis and induce cognitive impairment. We also review factors such as physical exercise and environmental stimulation that may protect against chemotherapy-induced neurogenic suppression and hippocampal neurotoxicity. Finally, we review pharmacological interventions that target the hippocampus and are designed to prevent or reduce the cognitive and neurotoxic side effects of chemotherapy.

Oroxylum Indicum ameliorates chemotherapy induced cognitive impairment.

While chemotherapy is the most effective therapeutic approach for treating a variety of cancer patients, commonly used chemotherapeutic agents, often induce several adverse effects. Escalating evidence indicates that chemotherapeutics, particularly doxorubicin (DOX) and cyclophosphamide (CPS), induce cognitive impairment associated with central nervous system toxicity. This study was performed to determine neuroprotective effects of Oroxylum indicum extract (OIE) in regard to preventing chemotherapy induced cognitive impairment (CICI) occurring after 4 cycles of DOX (2mg/kg) and CPS (50mg/kg) combination chemotherapy in male C57BL/6J mice. OIE significantly prevented the chemotherapy impaired short-term cognitive performance, exploratory behavior associated with cognitive performance, cognitive performance, and spatial learning and memory in the Y-maze, Open-Field, Novel Object Recognition, and Morris Water Maze tests, respectively. These data suggest that OIE protects from the CICI. OIE decreased the reactive oxygen species and lipid peroxide generated by the chemotherapy treatment in the brain, while also blocking the chemotherapy-induced glutathione depletion. These results establish that OIE exhibits potent antioxidant activity in chemotherapy treated mice. Notably, OIE significantly increased the Complex-I and Complex-IV activities in the brain, indicating that OIE enhances mitochondrial function in the brain. In silico analysis of the major active chemical constituents (Oroxylin A, Baicalein and Chrysin) of OIE indicated that OIE has a favorable absorption, distribution, metabolism and excretion (ADME) profile. Taken together, our results are consistent with the conclusion that OIE prevents CICI by counteracting oxidative stress and perhaps by improving mitochondrial function.

The Promise of Nutrient-Derived Bioactive Compounds and Dietary Components to Ameliorate Symptoms of Chemotherapy-Related Cognitive Impairment in Breast Cancer Survivors.

OPINION STATEMENT: One of the most burdensome symptoms reported by breast cancer patients is chemotherapy-related neurocognitive impairment. It is estimated that of the 11 million cancer survivors in the USA, 22% of them are breast cancer patients. The National Cancer Institute classified chemotherapy-related cognitive impairment (CRCI) as one of the most debilitating sequelae of cancer therapy, limiting this patient population from recommencing their lives prior to the diagnosis of breast cancer. Currently, there are no strategies that are established to prevent, mitigate, or treat CRCI. In addition to surviving cancer, quality of life is critical to cancer survivors. Based on the multiple and complex biological and psychosocial etiology, the varying manifestation and extent of cognitive decline documented in breast cancer survivors, possibly attributed to varying combinations of chemotherapy and dose and duration of therapy, multimodal interventions combining promising nutrient-derived bioactive compounds with antioxidant and anti-inflammatory properties, in addition to structured cognitive training and exercise regimens, can work synergistically to reduce inflammation and oxidative stress with significant improvement in cognitive function resulting in improvements in quality of life of breast cancer survivors.

Berberine ameliorates doxorubicin-induced cognitive impairment (chemobrain) in rats.

AIMS: Cognitive decline is one of the most challenging issues for cancer survivors undergoing doxorubicin (DOX) based chemotherapy. Oxidative stress and inflammation primarily through tumor necrosis factor-alpha (TNF-α) are considered the key contributors to DOX-induced chemobrain. Berberine (BBR) has attracted much interest because of its anti-oxidative, anti-inflammatory and anti-apoptotic actions. This study aimed to evaluate the potential neuroprotective effect of BBR in DOX-induced neurodegeneration and cognitive deficits. MATERIALS AND METHODS: Chemobrain was induced by DOX i.p. injection at the dose of 2 mg/kg, once/week, for four consecutive weeks. Rats were treated with BBR (100 mg/kg, p.o.) for 5 days/week for four consecutive weeks. KEY FINDINGS: BBR significantly attenuated behavioral defects in DOX-induced cognitive impairment. Besides, BBR reversed histopathological abnormalities. Mechanistically, it reversed DOX-induced neuroinflammation by attenuating NF-κB gene and protein expression in addition to diminishing expression of pro-inflammatory mediators (TNF-α and IL-1ß), as well as apoptotic related factors (Bax, Bcl2 and Bax/Bcl2 ratio). Additionally, BBR activated the anti-oxidative defense via upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and manganese superoxide dismutase (MnSOD). BBR improved synaptic plasticity through cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). These effects were related through the modulation of Sirtuin1 (SIRT1) expression. SIGNIFICANCE: BBR is highlighted to induce neuroprotection against DOX-induced cognitive decline through modulating brain growth factors and imposing an anti-inflammatory, anti-apoptotic and anti-oxidative effects.

C-phycocyanin Mitigates Cognitive Impairment in Doxorubicin-Induced Chemobrain: Impact on Neuroinflammation, Oxidative Stress, and Brain Mitochondrial and Synaptic Alterations.

Chemotherapy-induced cognitive impairment (CICI) is a common detrimental effect of cancer treatment, occurring in up to 75% of cancer patients. The widely utilized chemotherapeutic agent doxorubicin (DOX) has been implicated in cognitive decline, mostly via cytokine-induced neuroinflammatory and oxidative and mitochondrial damage to brain tissues. C-phycocyanin (CP) has previously been shown to have potent anti-inflammatory, antioxidant, and mitochondrial protective properties. Therefore, this present study was aimed to investigate the neuroprotective effects of CP against DOX-elicited cognitive impairment and explore the underlying mechanisms. CP treatment (50 mg/kg) significantly improved behavioral deficits in DOX-treated mice. Furthermore, CP suppressed DOX-induced neuroinflammation and oxidative stress, mitigated mitochondrial abnormalities, rescued dendritic spine loss, and increased synaptic density in the hippocampus of DOX-treated mice. Our results suggested that CP improves established DOX-induced cognitive deficits, which could be explained at least partly by inhibition of neuroinflammatory and oxidant stress and attenuation of mitochondrial and synaptic dysfunction.

Abrogating doxorubicin-induced chemobrain by immunomodulators IFN-beta 1a or infliximab: Insights to neuroimmune mechanistic hallmarks.

Chemobrain is a well-established clinical syndrome that impairs patient's daily function, in particular attentiveness, coordination and multi-tasking. Thus, it interferes with patient's quality of life. The putative pharmacological intervention against chemobrain relies on understanding the molecular mechanisms underlying it. This study aimed to examine the potential neuroprotective effects of two immunomodulators: Interferon-ß-1a (IFN-ß-1a), as well as Tumor necrosis function-alpha (TNF-α) inhibitor; Infliximab in doxorubicin (DOX)-induced chemobrain in rats. Besides, the current study targets investigating the possible molecular mechanisms in terms of neuromodulation and interference with different death routes controlling neural homeostasis. Herein, the two immunomodulators IFN-ß-1a at a dose of 300,000 units; s.c.three times per week, or Infliximab at a dose of 5 mg/kg/week; i.p. once per week were examined against DOX (2 mg/kg/w, i.p.) once per week for 4 consecutive weeks in rats.The consequent behavioral tests and markers for cognitive impairment, oxidative stress, neuroinflammation, apoptosis and neurobiological abnormalities were further evaluated. Briefly, IFN-ß-1a or Infliximab significantly protected against DOX-induced chemobrain. IFN-ß-1a or Infliximab ameliorated DOX-induced hippocampal histopathological neurodegenerative changes, halted DOX-induced cognitive impairment, abrogated DOX-induced mitochondrial oxidative, inflammatory and apoptotic stress, mitigated DOX-induced autophagic dysfunction and finally upregulated the mitophagic machineries. In conclusion, these findings suggest that either IFN-ß-1a or Infliximab offers neuroprotection against DOX-induced chemobrain which could be explained by their antioxidant, anti-inflammatory, pro-autophagic, pro-mitophagic and antiapoptotic effects. Future clinical studies are recommended to personalize either use of IFN-ß-1a or infliximab to ameliorate DOX-induced chemobrain.