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An update on neurobiological mechanisms involved in the development of chemotherapy-

induced cognitive impairment (CICI)

Laura Catalina Murillo Espitia

Departamento de Biología, Facultad de Ciencias, Pontificia Universidad Javeriana

laura.murillo@javeriana.edu.co

Abstract

Chemotherapy is one of the most effective treatments against cancer. However, its toxic non-

specificity affects both healthy and cancer cells. This toxicity generates side effects, being one of the

most recognized the chemotherapy-induced cognitive impairment (CICI). Patients following

chemotherapy report a decrease in cognitive abilities such as memory, learning, word finding and

executive functions. Here I present a literature review on the main neurobiological mechanisms

involved in CICI using a Boolean formula following the steps of the Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (Prisma) statement searching in several databases. It was

found that main mechanisms described in the literature to explain CICI include neurotoxicity,

decreased neurogenesis, loss of dendritic spines and dendritic complexity, altered neurotransmission,

disruption of glial cells, loss of myelination and cytokine dysregulation leading to neuroinflammation.

This review provides a general understanding of the neurobiological mechanisms underlying CICI

and possible therapeutic targets to prevented. Further research is needed on alternative mechanisms

related to the development and the severity of CICI and its prevention.

Key words: chemobrain, cognitive impairment, chemotherapy drugs, CICI.

1. Introduction

Cancer is one of the main causes of death worldwide (Ježek et al., 2021). In 2020, the World Health

Organization reported 19’292.789 new cancer cases, being breast cancer the most prevalent type

(World Health Organization, 2020). Hallmarks of these polygenic diseases are replicative

immortality, angiogenesis induction, resisting cell death, sustaining proliferative signaling, evading

growth suppressors, activating invasion and metastasis, cellular energetics dysregulation, genome

instability and mutation, eluding immune destruction, and tumor-promoting inflammation (Hanahan

& Weinberg, 2011). Due to cancer’s etiology complexity, each patient require different types of

treatment or a combination of them, being chemotherapy and radiotherapy among the main treatments

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given their effectiveness in increasing patients survival with different types of cancer (Wen et al.,

2021).

Several chemotherapeutic drugs are used in cancer treatment, bring classified by the mechanism of

action. Alkylating agents (cyclophosphamide, cisplatin, carboplatin) and nitrosoureas like carmustine

are DNA crosslinkers (Cheung-Ong et al., 2013), anti-metabolites such as fluorouracil and

methotrexate inhibit DNA synthesis, plant alkaloids (vincristine, paclitaxel, docetaxel) induce

apoptosis through DNA damage (Habli et al., 2017), anti-tumor antibiotics as doxorubicin and

mitoxantrone inhibits topoisomerase II (Castel et al., 2017), or inhibits the synthesis and repair

mechanisms of DNA (Bhattacharya & Mukherjee, 2015), all of them reducing viability of rapid

dividing cells. Nevertheless, an important issue of chemotherapy drugs is their effects on healthy and

cancer cells, inducing multiple side effects.

One side effect of chemotherapy of non-central nervous system cancers is known as “chemobrain”,

“chemo fog”, or Chemotherapy-Induced Cognitive Impairment (CICI), which manifest during or after

treatment and includes learning, memory, attention, and executive function impairment in varying

degrees (Kaplan et al., 2016; Shi et al., 2019). Epidemiological studies in the United States record

that as of 2019 there were 16.9 million cancer survivors (American Cancer Society, 2020). Within

survivors, the prevalence of cognitive impairment after chemotherapy is estimated to be 15%-75%,

and up to 17%-35% of them suffer long-term effects (Moore et al., 2019; Myers et al., 2008).

Common symptoms reported by patients suffering CICI include inability to solve problems, lack of

concentration, difficulty finding the right words when speaking, memory loss, learning disabilities,

impaired executive functions and processing speed (Moore et al., 2019; Ren, Boriero, et al., 2019);

other neurobehavioral changes affecting the patient's quality of life after chemotherapy are anxiety

and depression (Liao et al., 2018). Even when it has been reported that just having cancer diagnosis

can affect cognitive function, evidence supports that chemotherapy further alters proper cognitive

functioning (Joly et al., 2015).

Considering epidemiological studies, it can be expected that an increasing number of new cases of

cancer and chemobrain will be reported. In this regard, current research has been focusing on

understanding the neurobiological mechanisms underlying CICI and searching for therapeutic targets

(Nguyen & Ehrlich, 2020; Stankovic et al., 2020). Although some mechanisms underlying CICI have

been described, knowledge about effects of different chemotherapeutics on cognition is constantly

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growing. In this vein, this review aims to present a comprehensible update on the main

neurobiological mechanisms involved in CICI.

2. Methods

The literature review was developed following the steps of the Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (Prisma) statement (Liberati et al., 2009). First, several

databases were selected from the electronic sources provided by the Pontificia Universidad Javeriana

(Academic Search Complete, Google Scholar, Nature, ProQuest, ScienceDirect, Scopus,

SpringerLink, Taylor & Francis and Web of Science). Then, the Boolean search was performed with

the following formula: chemobrain AND mechanism AND biochemical AND cellular. Inclusion

criteria were as defined as follows: original articles or reviews in English, peer-reviewed, published

in the period 2012-2021, with clinical, in vivo, and in vitro study models. Additional articles were

identified from the reference lists of previously selected articles and chosen for further review; in this

case, the date of publication was not considered.

All previously obtained articles were reviewed and duplicates were excluded from the list. Other

exclusion criteria were as follows: articles that corresponded to abstracts or conference reports,

articles on neurodegenerative diseases, computational approaches, neurobehavioral changes, or

articles in which the chemotherapy regimen was not specified. Prisma flowchart depicts the process

for articles and reviews selection (Fig. 1). Subsequently, the selected articles were read and analyzed,

and the information was summarized in Table 1. Finally, in the results section each of the

neurobiological mechanisms listed in the table was briefly described.

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Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flowchart for articles and

reviews search process. 408 documents were identified with the Boolean search in the following databases: Academic

Search Complete = 39, Google Scholar =157, Nature = 2, ProQuest = 50, ScienceDirect = 22, Scopus = 122, SpringerLink

= 12, Taylor & Francis, = 3 and Web of Science = 1. Additional documents from the reference lists = 11. Finally, 283

records were screened and finally 52 articles were selected for full-text review. Created with BioRender.com.

3. Results

In this section it will be briefly described the main neurobiological mechanisms underlying CICI

found in the literature search (Table 1) including neurotoxicity, decreased neurogenesis, loss of

dendritic spines and dendritic complexity, altered neurotransmission, disruption of glial cells, loss of

myelination and cytokine dysregulation leading to neuroinflammation (Fig. 2).

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3.1 Neurobiological mechanisms

3.1.1 Neurotoxicity

Neurotoxicity is understood as the deleterious effect that a compound may have, or the indirect

metabolic alteration caused by that compound on the Central Nervous System (CNS) or peripheral

nervous system (PNS) (Pellacani & Eleftheriou, 2020). Notably, the CNS is integrated by two main

types of cells: neurons, and glial cells (astrocytes, oligodendrocytes, and microglia). The correct

functioning and development of CNS rely on the refined communication between these cells

(Pellacani & Eleftheriou, 2020), process that can be seriously impaired by chemotherapeutic agents.

Given that exogenous agents such as chemotherapeutic drugs have been reported to be toxic to the

nervous system and other organs such as, bone marrow and lungs, chemotherapeutics doses are

limited (Pellacani & Eleftheriou, 2020).

Specifically, it has been described in a murine model that intraperitoneal injections of

cyclophosphamide (CPA), cause histopathological damage in the cerebral cortex, characterized by

necrotic and apoptotic nuclei (Singh & Kumar, 2019). Additionally, it has been reported in a murine

model that exposure to CPA can change the expression of up to 200 genes in mice brains of their

progeny, suggesting that these changes in the transcriptomic profile may be affecting brain

development and function not only in the animal receiving the chemotherapy but also in its progeny

(Kovalchuk et al., 2018).

Similarly, intraperitoneal injections of paclitaxel in a murine model led an increase in apoptosis in

hippocampal neurons by increasing proinflammatory cytokines (Li et al., 2018). In addition, it has

also been reported that cisplatin induces mitochondrial dysfunction as evidenced by decreased

respiratory capacity and morphological alterations, events related to the poor performance of treated

animals in new object/place recognition (NOPRT) tests (Chiu et al., 2017). Furthermore, reduced

neuronal survival has also been reported using cisplatin in an in vitro model of cortical neurons

(English et al., 2020), in this particular case, astrocyte-mediated mitochondrial transfer induced a

recovery of cisplatin-treated neurons. Likewise, the cisplatin analog, carboplatin produces

mitochondrial damage and oxidative stress (Chiorazzi et al., 2015 reviewed in Pellacani &

Eleftheriou, 2020).

Also, the use of doxorubicin (DOX) induced histopathological damage showing nuclear pyknosis in

mice hippocampal neurons, particularly in the subiculum, fascia dentata and hilus, along with darker

cytoplasm and abnormal morphology (Shaker et al., 2021). Interestingly, in an in vitro assay

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differentiated SH-SY5Y human neuronal cell model, the use of mitoxantrone was described to be

more toxic than DOX, supported by viability assays and the observation of apoptotic nuclei. Further

assays revealed that cytotoxicity was mediated by depolarization of the mitochondrial membrane

potential after 48 hours of exposure to chemotherapeutics (Almeida et al., 2018).

On the other hand, it has also been documented that intermittent treatment with docetaxel significantly

increased LC3-II formation (a marker of autophagy) in the hippocampus of treated mice (Fardell

et al., 2014). These autophagy processes are crucial in CNS homeostasis as they allow the degradation

and clearance of malfunctioning organelles, toxins, and pathogens (Pellacani & Costa, 2018).

Moreover, the systemic administration of fluorouracil reduced the expression of the Brain-Derived

Neurotrophic Factor (BDNF) levels in rat hippocampus, an important protein involved in

neurodevelopment and learning and memory (Mustafa et al., 2008 reviewed in Banach & Juranek,

2017). Also, it has been recently reported that another chemotherapeutic drug, vincristine, cause

destruction of hippocampal tissue when administered unilaterally or bilaterally to mouse (Meléndez

et al., 2020).

Taken this evidence together, it is likely that neurotoxicity is a key mechanism underlying CICI as it

directly impairs the homeostasis and viability of CNS cells, mainly neurons in important brain areas

involved in cognitive processes. Apparently, neurotoxic effects rely on oxidative stress,

mitochondrial dysfunction, and apoptosis.

3.1.2 Diminishing neurogenesis

Neurogenesis is a complex process in which a wide range of cellular and molecular events occur to

generate fully mature postmitotic neurons. In the adult mammal brain neurogenesis has been

documented in different regions including the olfactory bulb, neocortex, striatum, and hippocampus

(Snyder, 2019). Notably, special emphasis has been given to hippocampal neurogenesis due to its

relationship with higher cognitive functions, especially with learning and memory (Kempermann

et al., 2015).

In this vein it has been reported in a murine model that intraperitoneal injections of

cyclophosphamide and doxorubicin, caused a 47% and 53% decrease in the number of immature

doublecortin (DCX)-labeled neurons, respectively, when compared to saline treated controls; also,

ectopic migration of these immature neurons was observed (Christie et al., 2012). A decrease in

neurons labeled simultaneously with NeuN (marker for mature neurons) and BrdU (marker for

proliferative cells) was also observed after treatment with these chemotherapeutics, suggesting that

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hippocampal neurogenesis was significantly impaired (Christie et al., 2012; Ikonomidou, 2018).

Similarly, the use of the CMF (cyclophosphamide, methotrexate and fluorouracil) regimen in an in

vivo model also resulted in a decrease of proliferative cells in the hippocampus, specifically in the

dentate gyrus (Briones & Woods, 2011).

Similar results have been observed after the systemic administration of fluorouracil, inducing a

decrease of DCX and BDNF positive cells in hippocampus (Mustafa et al., 2008 reviewed in Banach

& Juranek, 2017), and therefore indicating a disruption in hippocampal neurogenesis (Reviewed in

Ikonomidou, 2018). It should be noted that BDNF plays a critical role in the differentiation and

survival of new neurons, and reduction in its expression leads to memory deficits (Mustafa et al.,

2008).

Interestingly, it was reported that acute treatment with cisplatin causes an increase in apoptotic cells

in the CA1, CA3 and subgranular zone (SGZ) of the dentate gyrus in the hippocampus of treated male

rats (Andres et al., 2014). In the same study authors reported that cisplatin treatment resulted in the

depletion of neural stem cells (NSCs) cultured in vitro; however, NSCs were more resilient than

differentiated hippocampal neurons (Andres et al., 2014). Notably, antioxidant treatments can prevent

the deleterious effect of cisplatin and carmustine on hippocampal neurogenesis, suggesting that

oxidative stress is an important mechanism in this context (Reviewed in Ikonomidou, 2018; Reviewed

in Stankovic et al., 2020)..

Comparable whit these results, it was reported that intravenous injection of methotrexate in rats

significantly reduced DCX expression in the hippocampus. This effect was accompanied by a

decrease in BDNF and Nuclear factor erythroid-related factor (Nrf2) levels in both the hippocampus

and prefrontal cortex, both factors critical in the regulation of neurogenesis and subsequent

differentiation of NSCs (Kärkkäinen et al., 2014; Welbat et al., 2020). Decline in NSCs viability has

also been observed in paclitaxel treated cells in culture (Huehnchen et al., 2017).

As evidenced above, several chemotherapeutics diminish the expression of neurotrofic factors and

impaired neurogenesis in key areas for learning and memory, suggesting that impaired NSCs

production, migration and differentiation is a possible neurobiological mechanism underlying the

cognitive deterioration observed after the use of chemotherapeutics.

3.1.3 Loss of dendritic spines and arborizations

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Neuronal connectivity and function are highly related to the number of dendritic spines and dendritic

tree complexity (Andres et al., 2014). Dendritic spines are specialized protrusions that are generally

located in the excitatory synapses (Chidambaram et al., 2019). These tiny structures have been

reported as critical sites in synaptic plasticity, where their morphology and density are essential for

memory and learning processes (Chidambaram et al., 2019). Four types of dendritic spines have been

proposed based in their morphology: mushroom spines, thin spines, stubby spines, and cup-shaped

spines, while mushroom spines are considered the most stable thin spines are considered the least

stable (Chidambaram et al., 2019). The potential importance of dendritic spines in memory and

learning has been described from the point of view of long-term potentiation (LTP). In this process,

the spines with the highest activity are those that will be maintained over time (Kasai et al., 2010).

Similarly, it has also been documented that the complexity of the dendritic tree has an important role

in memory formation and consolidation (Alexander et al., 2018).

Specifically, intravenous injection of cyclophosphamide or doxorubicin on ovariectomized mice

induce a reduction in the density of stubby dendritic spines in the dentate gyrus (Flanigan et al., 2018).

Similarly, intraperitoneal injection of doxorubicin in mice decrease the density of dendritic spines

and synaptic density in neurons of the CA1 region of the hippocampus (Wang et al., 2021). Also, in

vivo and in vitro model, it was documented that treatment with cisplatin caused a reduction in the

density of dendritic spines and dendritic branches in apical and basal dendrites in pyramidal neurons

of the CA1 and CA3 regions of the hippocampus (Andres et al., 2014). The synaptic damage induced

by cisplatin was not reversible, even after five days post-treatment (Andres et al., 2014).

Similar to this, it has been described in a juvenile murine model that the intrathecal application of

methotrexate considerably affects the dendritic architecture and reduces the density of mushroom

dendritic spines in CA1, CA3 and dentate gyrus of the hippocampus (Alexander et al., 2018).

Consistent with these results, it was reported in another murine model that the intraperitoneal

application of docetaxel, doxorubicin, and cyclophosphamide (DAC) significantly eliminate dendritic

spines of medial prefrontal cortex neurons (Shi et al., 2019).

More complex effects were reported in CMF-treated animals that exhibited a significant increase in

the number of stubby spines and a decrease in the number of mushroom-shaped spines in the DG,

while in CA1 and CA3 regions of the hippocampus there was a significant increase in the density of

dendritic spines (Anderson et al., 2019). However, decreases in the number of branch points, dendritic

ends, dendritic length, and dendritic complexity were observed in CMF-treated animals.

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In addition, it has been described in an aged murine model that the use of intraperitoneal injections

of fluorouracil caused a decrease in the density of mushroom dendritic spines in the DG, while the

density of thin and stubby dendritic spines is increased. Accordingly, apical dendrites of pyramidal

neurons of the CA1 region showed decreased density of mushroom spines but increased density of

stubby spines; however, a decrease in thin spines was documented in the basal dendrites of pyramidal

neurons in CA3 (Groves et al., 2017). Also, it has been documented that fluorouracil negatively

affected dendritic complexity in DG neurons (Groves et al., 2017).

Taken together, these results indicate that chemotherapeutic treatment affects dendritic spine

dynamics and that there is also a tendency to decrease dendritic complexity in pyramidal neurons of

the hippocampus. One of the most marked trends was the decreased number of mushroom dendritic

spines and the increase in thin and stubby spines. Given that mushroom spines are the most stable

and the thin spines the least stable, changes in the density ratio of these spines could explain in part

the development of CICI.

3.1.4 Alterations in neurotransmission

Neuronal communication occurs via electrochemical gradient; the action potential travels through the

neuron cell body and generate neurotransmitter release to the synaptic cleft (Faber & Pereda, 2018).

It has been seen that the most important brain regions in cognition, such as the prefrontal cortex and

the hippocampus, are densely innervated with serotonergic, cholinergic and dopaminergic afferents.

Therefore, neurotransmitters such as serotonin, acetylcholine and dopamine (DA) are essential

modulators of memory and learning (Gonzalez-Burgos & Feriavelasco, 2008) (Levin, 2006). Also,

glutamate plays an important role in cognition, specifically in spatial memory, given that hippocampal

neurons are glutamatergic (Handra, 2019).

It has been described that intraperitoneal application of cisplatin-treatment induced a considerable

increase in brain acetylcholine levels, while generating a decrease in the relative expression levels

and activity of acetylcholinesterase (Arafa & Atteia, 2020). In contrast, in another in vivo model it

has been reported that the use of doxorubicin produces a reduction in the levels of acetylcholine in

both, hippocampus and prefrontal cortex (Ali et al., 2020). In this second study researchers found that

DOX treatment impaired learning and memory (Ali et al., 2020).

Also, decreased release of dopamine in the striatum was documented after intravenous application of

fluorouracil in a murine model, these findings were correlated with the decrease in attention shown

by these animals (Jarmolowicz et al., 2019). Similar results were obtained after treating animals with

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carboplatin; DA and serotonin release were negatively affected while DA uptake was decreased in

the striatum, these changes that correlate to the impairment in spatial learning exhibited by the

carboplatin-treated animals (Kaplan et al., 2016).

Additionally, it has been found that intraperitoneal application of doxorubicin generates a decrease

of DA and its extra-neuronal metabolite 3-methoxytyramine (3-MT) in both the frontal cortex and

hippocampus of treated animals compared to the saline control (Antkiewicz-Michaluk et al., 2016).

In parallel, another research group documented that doxorubicin application produced a slower

glutamate uptake in the frontal cortex, while the dentate gyrus produced a slower clearance of

glutamate and consequently an overflow of glutamate in this region (Thomas et al., 2017). All this

together affected the swimming speed of the doxorubicin-treated group; however this effect lasted

only 24 hours after administration (Thomas et al., 2017).

Because of the above results, it stands out that the different chemotherapeutic agents are affecting

different neurotransmitter systems which in turn are affecting cognitive processes such as memory

and learning, common symptoms presented by patients with CICI. Therefore, neurotransmitter

balance can be considered as an essential mechanism in the development of the phenomenon.

3.1.5 Disturbance in glial cells

As mentioned before, glial cells are important for the CNS functioning. Particularly, astrocytes have

been reported as the physical and metabolic support of neurons (Kıray et al., 2016). However, it has

been described that astrocytes are involved in many other processes. In particular, astrocytes have

been shown to play a key role in cognitive processing by contributing to synaptic transmission and

structural plasticity, where a bidirectional communication between neurons and astrocytes is

established (Santello et al., 2019). Accordingly, it has also been documented that both astrocytes and

microglia play an important role in the formation and pruning of synapses. Also, even when the main

role of microglia is to phagocytize apoptotic neuronal bodies and some synapses (Vainchtein &

Molofsky, 2020), in recently years, it has been reported that microglia modulates the formation of

new neurons in the hippocampus, regulate dendritic and axonal growth, and stimulate the formation,

modulation and relocation of synapses, processes necessary for memory formation (Rodríguez-

Iglesias et al., 2019).

Effects of microglial activation after the intraperitoneal administration of cyclophosphamide have

been observed in the hippocampus of male rats that show increased in ED1-positive cells (a marker

of microglial activation) in response to treatment; also, this effect seem to be related to impaired

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performance on novel place recognition (NORT) and contextual fear conditioning tests (Christie

et al., 2012).

In concurrence, in a male murine model it has been shown that intermittent intraperitoneal application

of docetaxel generates an increase in GFAP-positive astrocytes, indicating astrocyte activation. This

activation was seen at 48 hours after docetaxel administration and extended, at lower levels, up to 9

days after application. Furthermore, it was noted that docetaxel-treated animals performed worse in

the novel object recognition test (Fardell et al., 2014).

Also, oligodendrocyte survival result impaired in a dose-dependent after treatment of cells in culture

with cisplatin (Dietrich et al., 2006 reviewed in Stankovic et al., 2020). The same research group

reported similar results in an in vivo and in vitro models in which decreased oligodendrocyte survival

was evidenced by treatment with fluorouracil (Han et al., 2008).

Likewise, in a juvenile murine model it has been shown that peritoneal application of methotrexate

induces microglial activation, which in turn affects oligodendrocyte maturation dynamics and

increases astrocyte reactivity. Authors of these paper also reported that the reduction of microglia

restored tri-glial stability and cognitive function, assessed by the novel object recognition task

(Geraghty et al., 2019; Gibson et al., 2019). Importantly, other authors have also showed that

administration of doxorubicin induced astrocytic activation in the frontal cortex, striatum,

hippocampus, hypothalamus, and cerebellum. Finally, the authors suggested that these results

partially explained the cognitive impairment evidenced by a more unsatisfactory outcome in new

object recognition tests (Cardoso et al., 2020).

Taking together, these results reflect the enormous impact of chemotherapeutics on glial populations.

Particularly, the activation of astrocytes and microglia was evidenced. These is relevant since these

processes cause tissue damage due to the release of proinflammatory cytokines that in turn generate

neuroinflammation and ultimately neurodegeneration (Pekny et al., 2014).

3.1.6 Myelination loss

In the CNS, myelination is a complex and lifelong process in which oligodendrocytes wrap segments

of the axons of certain neurons. These segments become isolated and enable the saltatory action

potential, that is an evolutionary mechanism that had allowed faster conduction and processing of

information (Aggarwal et al., 2011; de Faria et al., 2019). Two types of myelination have been

described. The first is intrinsic myelination, which occurs independently of neuronal activity. The

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second is adaptive myelination, which is regulated and shaped by neuronal activity and is associated

with neuroplasticity, critical for learning (Bechler et al., 2018).

In a murine model, methotrexate exposure has been documented to decrease the cortical expression

of BDNF, which together with TrkB, is required for adaptive myelination (Geraghty et al., 2019).

Interestingly, BDNF expression is normalized after microglia depletion, although the underlying

mechanisms are not yet known (Geraghty et al., 2019; Gibson et al., 2019). Also, toxic effects on

CNS progenitor cells and non-dividing oligodendrocytes has been reported with the use of

fluorouracil both in vivo and in vitro (Han et al., 2008). Administration of fluorouracil generates a

delayed damage in myelin and axons, which can be observed up to 56 days after the completion of

the treatment, resulting in a myelinopathy that did not correlate with chronic inflammation or vascular

damage caused by the chemotherapeutic (Han et al., 2008).

Similarly, it has been documented that the use of CMF regimen generates a decrease in myelin basic

protein (MBP) and O4 (a pro-oligodendrocyte marker), as well as a decrease in both, the area covered

by myelin and reduced thickness of the sheath in the corpus callosum of female rats (Briones &

Woods, 2014). This study, however, correlate neuroinflammation with loss of myelination and

subsequent cognitive impairment (Briones & Woods, 2014).

Overall, these results indicate that chemotherapeutics also can negatively affect the myelination

process. This damage appears to be persistent despite the cessation of chemotherapeutics. It would

partially explain why some patients report that chemobrain symptoms persist years after completing

cycles of chemotherapy.

3.1.7 Cytokine dysregulation

Cytokines are part of cellular communication, playing a fundamental role in the development and

physiology of the CNS; for these reasons CNS is especially vulnerable to dysregulated cytokine

network, and some changes in the microenvironment due to diseases or external factors.

Chemotherapy frequently lead to inflammation, and chronic inflammation can lead to tissue damage

and cell infiltration in the CNS. The mentioned phenomena intertwine, generating a vicious cycle of

inflammatory damage plus tissue damage, eventually leading to neurodegeneration (Becher et al.,

2017).

It has been documented that the use of cyclophosphamide in a murine model generates alterations

among cytokines. Within the proinflammatory cytokines interleukin-1 (IL-1), tumor necrosis

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factor (TNF), and interleukin-6 (IL-6) were found to be significantly elevated in the hippocampus

and cortex, while the anti-inflammatory cytokine IL-10 was significantly decreased. In sum, this

imbalance induces a neuroinflammatory environment that contributes to cognitive impairment,

evidenced by increased immobility time in the forced swim test (FST) and decreased performance in

the latency retention transfer test observed in treated animals. These tests evaluate the extent of

behaviors associated with depression and memory acquisition and retention, respectively (Iqubal

et al., 2019).

In agreement, it has been reported that the application of cisplatin generates IL-1, and TNF,

elevation in the hippocampus of a murine model. Along with these results, it was also described that

treated animals performed worse in the NORT tests and in the motor coordination test (Jangra et al.,

2016). Similarly, other authors reported in another murine model that the application of cisplatin

caused a significant increase in the level of both TNF and IL-6 in the cerebral cortex of the treated

group (Arafa & Atteia, 2020). Likewise, it has been reported that intraperitoneal application of

fluorouracil in an aged murine model increased the levels of IL-1, IL-2, IL-3, IL-4, IL-5, and IL-17

in the hippocampus after one month of treatment, which was related to detrimental effects on mature

hippocampal neurons (Groves et al., 2017).

Furthermore, other researchers have described that chronic intraperitoneal application of paclitaxel

in a male murine model elevates levels of the proinflammatory cytokines TNF and IL-1, in the

hippocampus, and these results were related to the subsequent decrease in spatial memory of treated

animals by increasing escape latency times in the Morris Water Maze (MWM) test (Li et al., 2018).

Notably, treatment with the bleomycin, etoposide, and cisplatin (BEP) regimen in patients with

testicular cancer (TC) also produced a significant increase in TNF levels compared to the group that

also had TC but did not receive BEP treatment. In this study, elevated TNF levels were associated

with poorer cognitive performance (Amidi et al., 2017).

Moreover, administration of doxorubicin generates a dramatic increase in the levels of the

proinflammatory cytokines TNF and IL-17, while the level of the anti-inflammatory cytokine IL-

10 declines in the hippocampus of treated animals. Treated animals also showed a reduction in short-

term memory as measured by the spontaneous alternation test (SAP) (Wahdan et al., 2020).

Consistent with this, in another murine model in which DOX was applied intraperitoneally, an

overexpression of TNF levels was evidenced in the brain (Tabaczar et al., 2017). Similarly, in a

female OVX murine model, it was reported that the application of the regimen doxorubicin and

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cyclophosphamide (AC) produced in the hippocampus a significant elevation of the cytokines IL-2,

IL-3, IL-4, IL-6, IL-10, IL-1ra, IL-17 and TNF (Bagnall-Moreau et al., 2019).

In addition, it has been reported that the use of the CMF regimen in an aged female murine model

generated increased levels of the proinflammatory cytokines TNF and IL-1b but reduced levels of

the anti-inflammatory cytokine IL-10 in the corpus callosum. Intriguingly, after one month of

cessation of treatment with the CMF regimen, the treated animals exhibited a worse performance in

memory and discrimination tests (Briones & Woods, 2014). Similar results were obtained with the

DAC regimen in which levels of the proinflammatory cytokines TNF and IL-6 were significantly

increased, but levels of the anti-inflammatory cytokine IL-4 and IL-10 were decreased in the whole

brain, especially in the prefrontal cortex and hippocampus of a female murine model (Shi et al., 2019).

Considering the evidence, chemotherapeutics promotes an imbalance between proinflammatory and

anti-inflammatory cytokines. Remarkable, it was documented that regardless of the chemotherapeutic

used, the cytokine frequently found to be elevated was TNF. This finding is important since it has

been described in the literature that the expression of this cytokine is related to increased oxidative

stress and mitochondrial dysfunction, which decreased in a TNF null model (Ren et al., 2019).

Additionally, it has also been documented that the elevation of reactive oxygen species (ROS) and

consequently of proinflammatory cytokines generate physical damage to the blood-brain barrier

(BBB), which subsequently contributes to the entry of small concentrations of chemotherapeutics that

normally do not have the capacity to pass the BBB, as is the case of Dox (Ren et al., 2019).

Finally, the described mechanisms show the different effects of chemotherapeutic agents that directly

or indirectly are affecting the communication or function of important brain regions involved in

cognition, such as the prefrontal cortex, hippocampus and striatum (Gonzalez-Burgos & Feriavelasco,

2008). For this reason, further research should continue to explore the short- and long-term effects of

chemotherapeutics, as this will also help in the development of therapeutic strategies.

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Figure 2. Main neurobiological mechanisms involved in the development of Chemotherapy-Induced Cognitive

Impairment (CICI). The blue lines indicate mechanisms occurring in the prefrontal cortex, the green lines indicate

mechanisms occurring in the hippocampus, the orange line indicates processes occurring in the corpus callosum and the

red line indicates processes occurring in the cerebellum. Created with BioRender.com.

3.2 Future directions

Given that most of the original articles here presented reported results obtained in healthy murine

models, it is important to validate this results in cancer models, rarely contemplated, in order to dissect

cognitive impairment induced by chemotherapy from the effects induced by the disease itself.

In addition, during the review, it became evident that some murine models used only males or only

females or only ovariectomized females. In these cases, valuable information about the effect of

chemotherapeutics in the groups that are not under consideration could be missed. For this reason, it

would be enlightening if more controls could be considered within the experimental design in order

to have a more global view of the obtained results.

17

Conclusion

In conclusion, chemotherapy-induced cognitive impairment is a complex phenomenon mediated by

altered neurobiological mechanisms, among which neurotoxicity, decreased neurogenesis, loss of

spines and dendritic complexity, altered neurotransmission, disruption of glial cells, loss of

myelination and cytokine dysregulation leading to neuroinflammation were highlighted. It should be

made clear that it is still necessary to elucidate what other mechanisms are involved in the

development of chemobrain. Therefore, more research is needed, hopefully including cancer models

in their experimental design, to understand this problem globally.

Acknowledgements

I would especially like to thank my family, especially my parents for all the support and love they

have given me throughout my career and my life. I love you with all my heart.

To my director Sonia Luz Albarracin for all these years of dedication and for giving me the

opportunity to be part of such a special research group.

Acknowledgement to the Ecosistema Científico - Colombia Científica " Generación de alternativas

terapéuticas en cáncer a partir de plantas a partir de plantas a través de procesos de investigación y

desarrollo traslacional, articulados en sistemas de valor sostenibles ambiental y económicamente"

financed by Banco Mundial.

To my friends who have supported me so much in good and difficult moments, especially Andrés

Pascagaza, Jose Velasco, Viviana Vargas, and Juan Diego Tovar.

To incredible people like Ana Lucía Rangel, Laura Girón and Maria Alejandra Ariza for their great

support and affection during the last semesters.

To my friends since the first semester for so many good memories, Daniel Botiva y Klaus Lubinus.

To Jhon Sutachan and other members of the Neurobiochemistry laboratory from whom I have learned

so many things during all these years.

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