Chemobrain in blood cancers: How chemotherapeutics interfere with the brain's structure and functionality, immune system, and metabolic functions.

Cancer treatment brings about a phenomenon not fully clarified yet, termed chemobrain. Its strong negative impact on patients' well-being makes it a trending topic in current research, interconnecting many disciplines from clinical oncology to neuroscience. Clinical and animal studies have often reported elevated concentrations of proinflammatory cytokines in various types of blood cancers. This inflammatory burst could be the background for chemotherapy-induced cognitive deficit in patients with blood cancers. Cancer environment is a dynamic interacting system. The review puts into close relationship the inflammatory dysbalance and oxidative/nitrosative stress with disruption of the blood-brain barrier (BBB). The BBB breakdown leads to neuroinflammation, followed by neurotoxicity and neurodegeneration. High levels of intracellular reactive oxygen species (ROS) induce the progression of cancer resulting in increased mutagenesis, conversion of protooncogenes to oncogenes, and inactivation of tumor suppression genes to trigger cancer cell growth. These cell alterations may change brain functionality, as well as morphology. Multidrug chemotherapy is not without consequences to healthy tissue and could even be toxic. Specific treatment impacts brain function and morphology, functions of the immune system, and metabolism in a unique mixture. In general, a chemo-drug's effects on cognition in cancer are not direct and/or in-direct, usually a combination of effects is more probable. Last but not least, chemotherapy strongly impacts the immune system and could contribute to BBB disruption. This review points out inflammation as a possible mechanism of brain damage during blood cancers and discusses chemotherapy-induced cognitive impairment.

Nose to brain delivery of naringin-loaded chitosan nanoparticles for potential use in oxaliplatin-induced chemobrain in rats: impact on oxidative stress, cGAS/STING and HMGB1/RAGE/TLR2/MYD88 inflammatory axes.

OBJECTIVES: Oxaliplatin induces chemobrain in cancer patients/survivors. Nutraceutical naringin has antioxidant and anti-inflammatory properties with low oral bioavailability. Our aim was to formulate naringin in chitosan nanoparticles for nose to brain delivery and assess its neuroprotective effect against oxaliplatin-induced chemobrain in rats. METHODS: Naringin chitosan nanoparticles were prepared by ionic gelation. Rats were administered oral naringin (80 mg/kg), intranasal naringin (0.3 mg/kg) or intranasal naringin-loaded chitosan nanoparticles (0.3 mg/kg). Naringin's neuroprotective efficacy was assessed based on behavioral tests, histopathology, and measuring oxidative stress and inflammatory markers. RESULTS: Selected nanoparticles formulation showed drug loading of 5%, size of 150 nm and were cationic. Intranasal naringin administration enhanced memory function, inhibited hippocampal acetylcholinesterase activity, and corrected oxaliplatin-induced histological changes. Moreover, it reduced malondialdehyde and elevated reduced glutathione hippocampal levels. Furthermore, it decreased levels of inflammatory markers: NF-kB and TNF-α by 1.25-fold. Upstream to this inflammatory status, intranasal naringin downregulated the hippocampal protein levels of two pathways: cGAS/STING and HMGB1/RAGE/TLR2/MYD88. CONCLUSION: Intranasal naringin-loaded chitosan nanoparticles showed superior amelioration of oxaliplatin-induced chemobrain in rats at a dose 267-fold lower to that administered orally. The potential involvement of cGAS/STING and HMGB1/RAGE/TLR2/MYD88 pathways in the mechanistic process of either oxaliplatin-induced chemobrain or naringin-mediated neuroprotection was evidenced.

Functional Imaging of Chemobrain: Usefulness of Nuclear Medicine in the Fog Coming After Cancer.

The impact of chemotherapy on brain functionality has been widely investigated from a clinical perspective, and there is a consensus on a significant impairment of multiple cognitive domains affecting cancer patients after treatment. Nuclear medicine offers a variety of biomarkers for evaluating possible effects of chemotherapy on the brain and for depicting brain changes after chemotherapy. This review summarizes the most relevant findings on brain imaging in patients undergoing chemotherapy for the most common oncologic diseases. The literature published to date offers exciting results on several radiolabeled compounds, from the more common imaging of glucose metabolism to neuroinflammation. This review also provides a general overview of the literature concerning clinical features and the physiopathologic basis of chemotherapy-related cognitive impairment.

Role of Cytokines in Chemotherapy-related Cognitive Impairment of Breast Cancer Patients: A Systematic Review.

BACKGROUND: Cognitive impairment is one of the most common problems experienced by patients receiving chemotherapy, and evidence suggests that cytokines might play an important role. Various studies were conducted to evaluate the role of cytokines in chemotherapy-related cognitive impairment (CRCI). However, the association between CRCI due to cytokines is not well-established. Thus, this systematic review aims to assess the role of cytokines in CRCI in breast cancer patients. METHODS: This systematic review was conducted according to the Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA) guidelines. An intense literature search was carried out for inclusion criteria in major databases, including PubMed and Clinicaltrials.gov, in August 2021. Studies assessing cognitive parameters through objective and subjective assessment in breast cancer patients receiving chemotherapy were included. RESULTS: A total of 4052 studies were identified, and 15 studies were included in this systematic review. We found that IL-6, IL-1ß, and TNF-α were associated with varying degrees of cognitive impairment in breast cancer patients receiving chemotherapy. CONCLUSION: This systematic review showed a correlation between various cytokines and chemotherapy- associated cognitive decline in breast cancer patients.

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.

Chemotherapy-induced cognitive impairment: focus on the intersection of oxidative stress and TNFα.

Chemotherapy-induced cognitive impairment (CICI) has been observed in a large fraction of cancer survivors. Although many of the chemotherapeutic drugs do not cross the blood-brain barrier, following treatment, the structure and function of the brain are altered and cognitive dysfunction occurs in a significant number of cancer survivors. The means by which CICI occurs is becoming better understood, but there still remain unsolved questions of the mechanisms involved. The hypotheses to explain CICI are numerous. More than 50% of FDA-approved cancer chemotherapy agents are associated with reactive oxygen species (ROS) that lead to oxidative stress and activate a myriad of pathways as well as inhibit pathways necessary for proper brain function. Oxidative stress triggers the activation of different proteins, one in particular is tumor necrosis factor alpha (TNFα). Following treatment with various chemotherapy agents, this pro-inflammatory cytokine binds to its receptors at the blood-brain barrier and translocates to the parenchyma via receptor-mediated endocytosis. Once in brain, TNFα initiates pathways that may eventually lead to neuronal death and ultimately cognitive impairment. TNFα activation of the c-jun N-terminal kinases (JNK) and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways may contribute to both memory decline and loss of higher executive functions reported in patients after chemotherapy treatment. Chemotherapy also affects the brain's antioxidant capacity, allowing for accumulation of ROS. This review expands on these topics to provide insights into the possible mechanisms by which the intersection of oxidative stress and TNFΑ are involved in chemotherapy-induced cognitive impairment.

Elevated Oxidative Stress and DNA Damage in Cortical Neurons of Chemotherapy Patients.

The unintended neurologic sequelae of chemotherapy contribute to significant patient morbidity. Chemotherapy-related cognitive impairment (CRCI) is observed in up to 80% of cancer patients treated with chemotherapy and involves multiple cognitive domains including executive functioning. The pathophysiology underlying CRCI and the neurotoxicity of chemotherapy is incompletely understood, but oxidative stress and DNA damage are highly plausible mechanisms based on preclinical data. Unfortunately, validating pathways relevant to CRCI in humans is limited by an absence of relevant neuropathologic studies of patient brain tissue. In the present study, we stained sections of frontal lobe autopsy tissue from cancer patients treated with chemotherapy (n = 15), cancer patients not treated with chemotherapy (n = 10), and patients without history of cancer (n = 10) for markers of oxidative stress (nitrotyrosine, 4-hydroxynonenal) and DNA damage (pH2AX, pATM). Cancer patients treated with chemotherapy had increased staining for markers of oxidative stress and DNA damage in frontal lobe cortical neurons compared to controls. We detected no statistically significant difference in oxidative stress and DNA damage by the duration between last administration of chemotherapy and death. The study highlights the potential relevance of oxidative stress and DNA damage in the pathophysiology of CRCI and the neurotoxicity of chemotherapy.

Donepezil Protects Against Doxorubicin-Induced Chemobrain in Rats via Attenuation of Inflammation and Oxidative Stress Without Interfering With Doxorubicin Efficacy.

Although doxorubicin (Dox) is an effective chemotherapy medication used extensively in the treatment of breast cancer, it frequently causes debilitating neurological deficits known as chemobrain. Donepezil (DPZ), an acetylcholinesterase inhibitor, provides therapeutic benefits in various neuropathological conditions. However, comprehensive mechanistic insights regarding the neuroprotection of DPZ on cognition and brain pathologies in a Dox-induced chemobrain model remain obscure. Here, we demonstrated that Dox-treated rats manifested conspicuous cognitive deficits and developed chemobrain pathologies as indicated by brain inflammatory and oxidative insults, glial activation, defective mitochondrial homeostasis, increased potential lesions associated with Alzheimer's disease, disrupted neurogenesis, loss of dendritic spines, and ultimately neuronal death through both apoptosis and necroptosis. Intervention with DPZ co-treatment completely restored cognitive function by attenuating these pathological conditions induced by DOX. We also confirmed that DPZ treatment does not affect the anti-cancer efficacy of Dox in breast cancer cells. Together, our findings suggest that DPZ treatment confers potential neuroprotection against Dox-induced chemobrain.

Pharmacological rescue of cognitive function in a mouse model of chemobrain.

BACKGROUND: After chemotherapy, many cancer survivors suffer from long-lasting cognitive impairment, colloquially known as "chemobrain." However, the trajectories of cognitive changes and the underlying mechanisms remain unclear. We previously established paclitaxel-induced inositol trisphosphate receptor (InsP3R)-dependent calcium oscillations as a mechanism for peripheral neuropathy, which was prevented by lithium pretreatment. Here, we investigated if a similar mechanism also underlay paclitaxel-induced chemobrain. METHOD: Mice were injected with 4 doses of 20 mg/kg paclitaxel every other day to induced cognitive impairment. Memory acquisition was assessed with the displaced object recognition test. The morphology of neurons in the prefrontal cortex and the hippocampus was analyzed using Golgi-Cox staining, followed by Sholl analyses. Changes in protein expression were measured by Western blot. RESULTS: Mice receiving paclitaxel showed impaired short-term spatial memory acquisition both acutely 5 days post injection and chronically 23 days post injection. Dendritic length and complexity were reduced in the hippocampus and the prefrontal cortex after paclitaxel injection. Concurrently, the expression of protein kinase C α (PKCα), an effector in the InsP3R pathway, was increased. Treatment with lithium before or shortly after paclitaxel injection rescued the behavioral, cellular, and molecular deficits observed. Similarly, memory and morphological deficits could be rescued by pretreatment with chelerythrine, a PKC inhibitor. CONCLUSION: We establish the InsP3R calcium pathway and impaired neuronal morphology as mechanisms for paclitaxel-induced cognitive impairment. Our findings suggest lithium and PKC inhibitors as candidate agents for preventing chemotherapy-induced cognitive impairment.

Do neprilysin inhibitors walk the line? Heart ameliorative but brain threatening!

Sacubitril/valsartan (Entresto™; LCZ696) is the first angiotensin receptor-neprilysin inhibitor (ARNI) drug approved by the US and EU for heart failure (HF) and especially recommended for hypertensive HF (HHF). Sacubitril inhibits the enzyme neprilysin (NEP) which produces both beneficial and adverse effects in the human body. While LCZ696 causes beneficial cardiovascular effects, it may induce memory and cognitive dysfunction, or even exacerbate Alzheimer's disease (AD). This article reviewed data reported by experimental and clinical studies that examined NEP inhibitors and their dementia-related side effects. Based on the literature, LCZ696 increases the risk of memory and cognitive dysfunctions, and clinical trials failed to show compelling evidence for LCZ696 safety for the brain. Together, it was concluded that more experimental and clinical studies with particular focus on LCZ696 side effects on ß-amyloid (Aß) degradation are needed to assess LCZ696 safety for the cognitive function, especially in case of long-term administration.

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.

Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice.

Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the quality of life of an increasing number of cancer survivors. The underlying mechanisms are not fully understood and there is no effective treatment. We show here that cisplatin treatment of mice not only caused cognitive dysfunction but also impaired sensorimotor function. These functional deficits are associated with reduced myelin density and complexity in the cingulate and sensorimotor cortex. At the ultrastructural level, myelin abnormalities were characterized by decompaction. We used this model to examine the effect of bexarotene, an agonist of the RXR-family of nuclear receptors. Administration of only five daily doses of bexarotene after completion of cisplatin treatment was sufficient to normalize myelin density and fiber coherency and to restore myelin compaction in cingulate and sensorimotor cortex. Functionally, bexarotene normalized performance of cisplatin-treated mice in tests for cognitive and sensorimotor function. RNAseq analysis identified the TR/RXR pathway as one of the top canonical pathways activated by administration of bexarotene to cisplatin-treated mice. Bexarotene also activated neuregulin and netrin pathways that are implicated in myelin formation/maintenance, synaptic function and axonal guidance. In conclusion, short term treatment with bexarotene is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance. These encouraging findings warrant further studies into potential clinical translation and the underlying mechanisms of bexarotene for chemobrain.

Post-chemotherapy cognitive impairment in hematological patients: current understanding of chemobrain in hematology.

Introduction: Cognitive impairment caused by chemotherapies, a condition known as chemobrain, is a possible side effect that affects alertness, learning, memory, and concentration.Areas covered: Chemobrain has been principally investigated as a possible side-effect among cancer patients. However, numerous drugs used to treat hematological malignancies can determine the appearance of chemobrain. In this review, we have examined some commonly used drugs for the treatment of hematological malignancies which are known to have a deleterious action on cognitive functions.Numerous mechanisms have been suggested, comprising the direct neurotoxicity of chemotherapeutic drugs, oxidative stress, genetic predisposition, cytokine-provoked damage, histone modifications, immune alteration, and the action of chemotherapeutic on trophic factors and structural proteins of brain cells.Expert commentary: Cognitive dysfunction provoked by the treatment of hematological diseases is an actual challenge in clinical practice. Actually, there are no totally efficient and innocuous treatments for this syndrome. It is important that further investigations specify the existence of predictors and gravity factors to pre- and post-therapy cognitive change and identify the influence of tumor treatments on the cognitive alterations in long-term, cancer survivors. Moreover, future studies are needed to analyze the interactions between genetic risk, amyloid accumulation, intrinsic brain networks, and chemotherapy.

Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer.

Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health.We used an in vitro system in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics that were characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in neurons that had received mitochondria from astrocytes which underlines the importance of mitochondrial transfer. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. We show that siRNA-mediated knockdown of the Rho-GTPase Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics.In conclusion, we showed that transfer of mitochondria from astrocytes to neurons rescues neurons from the damage induced by cisplatin treatment. Astrocytes are far more resistant to cisplatin than cortical neurons. We propose that transfer of functional mitochondria from astrocytes to neurons is an important repair mechanism to protect the vulnerable cortical neurons against the toxic effects of cisplatin.