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Brain Sciences
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Chemotherapy-Associated Brain Damage—Translational Insights from Pre-Clinical and Clinical Research
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Chemotherapy-Associated Brain Damage—Translational Insights from Pre-Clinical and Clinical Research

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuropharmacology and Neuropathology".

Deadline for manuscript submissions: 20 March 2027 | Viewed by 1839

Editor

Dr. Nikola Stojanović

E-Mail Website
Guest Editor
Center for Mental Health Protection, University Clinical Centre Niš, 18000 Niš, Serbia
Interests: psychiatry; neurosciences; pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chemotherapeutic agents, while indispensable in the treatment of malignant diseases, are increasingly recognized for their potential to induce damage to the central nervous system (CNS), in part through disruption of the blood–brain barrier (BBB), which maintains neuronal homeostasis. Many chemotherapeutic drugs, e.g., methotrexate, doxorubicin, can compromise BBB integrity through direct cytotoxic effects on endothelial cells, induction of oxidative stress, activation of matrix metalloproteinases, and inflammatory signaling cascades. Such alterations increase permeability, allowing the entry of neurotoxic molecules, peripheral immune cells, and inflammatory mediators into the brain parenchyma. In parallel, some agents exert direct neurotoxic effects independent of BBB disruption, including mitochondrial dysfunction, DNA damage, impaired axonal transport, and demyelination. These processes may target neurons, oligodendrocytes, astrocytes, and microglia, resulting in synaptic loss, white matter abnormalities, and altered neurotransmitter balance. Clinically, these pathological changes manifest as “chemobrain” or chemotherapy-induced cognitive impairment, characterized by deficits in attention, memory, executive function, and processing speed, and in severe cases, encephalopathy, seizures, or long-term neurodegeneration. Understanding the mechanisms of BBB and CNS injury is of critical importance as the incidence of neurotoxic side effects is expected to rise with improved cancer survival rates. Preventive and management strategies should focus on the early detection of BBB dysfunction, for example, via neuroimaging biomarkers or cerebrospinal fluid analysis, alongside neuroprotective interventions such as antioxidant supplementation, anti-inflammatory agents, or BBB-stabilizing compounds.

Addressing this problem requires a multidisciplinary approach that combines mechanistic understanding, preventive measures, and therapeutic interventions to safeguard the structural and functional integrity of the nervous system during and after cancer treatment. Thus, this Special Issue aims to collect preclinical research elucidating molecular pathways linking chemotherapy to BBB disruption and neural injury, which could potently lead to the development of pharmacological agents that protect CNS structures without diminishing the antitumor efficacy of chemotherapeutic agent. Further, clinical investigations combining neurologic, oncologic and psychiatric approaches in order to address this topic are of great value.

Dr. Nikola Stojanović
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Brain Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chemotherapeutics
  • brain damage
  • brain fog
  • translation studies
  • preventing brain damage

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Published Papers (3 papers)

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Research

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15 pages, 1102 KB  
Article
Morphological and Biochemical Changes in Rat Hippocampal Tissue Following Exposure to Different Doses of Cisplatin
by Milorad Antić, Vladimir Antić and Dušan Sokolović
Brain Sci. 2026, 16(7), 740; https://doi.org/10.3390/brainsci16070740 - 13 Jul 2026
Viewed by 401
Abstract
Background/Objectives: Cisplatin (CP) is a platinum-based chemotherapeutic agent associated with neurotoxicity and cognitive impairment. Due to its high metabolic activity and sensitivity to oxidative stress, the hippocampus represents a particularly vulnerable brain structure. The present study evaluated dose-dependent hippocampal alterations [...] Read more.
Background/Objectives: Cisplatin (CP) is a platinum-based chemotherapeutic agent associated with neurotoxicity and cognitive impairment. Due to its high metabolic activity and sensitivity to oxidative stress, the hippocampus represents a particularly vulnerable brain structure. The present study evaluated dose-dependent hippocampal alterations following single-dose cisplatin administration in rats using biochemical, histopathological, and morphometric analyses. Methods: Male Wistar rats were divided into four groups (n = 8): control and cisplatin-treated groups receiving single intraperitoneal doses of 8, 9, or 10 mg/kg. Five days after treatment, hippocampal tissue was analyzed for oxidative stress and inflammatory, apoptotic, and morphological changes. Results: Cisplatin administration significantly increased TBARS and AOPP levels, indicating enhanced lipid and protein oxidation. Elevated hippocampal TNF-α, IL-6, and IL-1β levels demonstrated activation of inflammatory pathways, particularly in animals receiving 9 and 10 mg/kg cisplatin. Higher doses additionally increased Bax/Bcl-2 ratio, caspase-3 content, and DNase I/II activity, consistent with enhanced apoptotic signaling. Histopathological examination revealed neuronal degeneration, pyknotic nuclei, pericellular halo formation, and progressive disruption of hippocampal cytoarchitecture, while morphometric analysis demonstrated significant alterations in neuronal nuclear surface area, predominantly in the 10 mg/kg group. Conclusions: These findings demonstrate that acute cisplatin exposure induces oxidative, inflammatory, apoptotic, and structural progressive hippocampal injury with a threshold-like increase in several endpoints at higher cisplatin doses, with 10 mg/kg producing the most pronounced neurotoxic effects. Full article
(This article belongs to the Special Issue Chemotherapy-Associated Brain Damage—Translational Insights from Pre-Clinical and Clinical Research)
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Review

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23 pages, 673 KB  
Review
Working Memory Impairment Induced by Chemotherapy—A Narrative Review
by Nikola M. Stojanović, Mihajlo Marjanović, Milan N. Petković, Ivana Kostić Petrović and Milica Radić
Brain Sci. 2026, 16(8), 805; https://doi.org/10.3390/brainsci16080805 - 30 Jul 2026
Viewed by 378
Abstract
Chemotherapy-associated cognitive impairment (CACI) is a common long-term complication of cancer treatment that predominantly affects attention, executive function, information processing, and working memory. Although considerable progress has been made in understanding its molecular basis, the relationship between chemotherapy-induced neurobiological alterations and the functional [...] Read more.
Chemotherapy-associated cognitive impairment (CACI) is a common long-term complication of cancer treatment that predominantly affects attention, executive function, information processing, and working memory. Although considerable progress has been made in understanding its molecular basis, the relationship between chemotherapy-induced neurobiological alterations and the functional organization of working memory remains incompletely understood. This narrative review aims to integrate current evidence on the neuroanatomical organization of working memory, the molecular mechanisms underlying CACI, and neuroimaging findings in patients receiving chemotherapy. The review summarizes current knowledge regarding mitochondrial dysfunction, oxidative stress, neuroinflammation, blood–brain barrier disruption, purinergic signaling, and chemotherapy-specific mechanisms of central nervous system injury. Furthermore, the principal mechanisms by which commonly used chemotherapeutic agents reach or indirectly affect the brain are discussed. Clinical neuroimaging findings from selected malignancies are interpreted within the framework of the four-component model of working memory, including the visuospatial sketchpad, phonological loop, central executive, and episodic buffer. Current evidence indicates that chemotherapy induces structural and functional alterations involving the prefrontal cortex, parietal cortex, hippocampus, insula, anterior cingulate cortex, angular gyrus, and associated neural networks. These changes are accompanied by disturbances in executive control, visuospatial processing, verbal working memory, and multimodal information integration. However, considerable heterogeneity among available studies and the difficulty in distinguishing cancer-related from chemotherapy-induced cognitive impairment remain major limitations. By integrating molecular, neuroanatomical, and neuroimaging evidence, this review proposes a conceptual framework linking chemotherapy-induced brain alterations with dysfunction of specific working memory components. Future longitudinal studies combining multimodal neuroimaging, molecular biomarkers, and standardized neuropsychological assessment are needed to identify chemotherapy-specific patterns of cognitive dysfunction and support the development of personalized preventive and therapeutic strategies for cancer survivors. Full article
(This article belongs to the Special Issue Chemotherapy-Associated Brain Damage—Translational Insights from Pre-Clinical and Clinical Research)
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28 pages, 1578 KB  
Review
Chemotherapy-Induced Brain Damage: Mechanisms and Insights from Rodent Models
by Milica Veljković, Tanja Džopalić, Pavle Ranđelović, Lidija Popović Dragonjić, Jelena Milenković and Ivan Ilić
Brain Sci. 2026, 16(7), 750; https://doi.org/10.3390/brainsci16070750 - 15 Jul 2026
Viewed by 450
Abstract
Background/Objectives: Chemotherapy-induced cognitive impairment, colloquially known as chemobrain, affects a substantial proportion of cancer patients. Preclinical rodent models help clarify underlying drug-specific neurotoxic effects, as well as histological, biochemical, molecular, and behavioral mechanisms. Methods: We conducted a narrative review of animal studies examining [...] Read more.
Background/Objectives: Chemotherapy-induced cognitive impairment, colloquially known as chemobrain, affects a substantial proportion of cancer patients. Preclinical rodent models help clarify underlying drug-specific neurotoxic effects, as well as histological, biochemical, molecular, and behavioral mechanisms. Methods: We conducted a narrative review of animal studies examining cognitive dysfunction following treatment with commonly used chemotherapeutic agents, including doxorubicin, cisplatin, cyclophosphamide, methotrexate, 5-fluorouracil, paclitaxel, and docetaxel. The review focused on behavioral and cognitive outcomes, and experimental parameters such as rodent models and dosing regimens. Results: Across studies, chemotherapeutic exposure has had a consistent negative effect on short-term and working memory, learning and other cognitive domains, with impairments being often mild and detectable even at doses not causing apparent systemic toxicity. Histological analyses revealed reduced neurogenesis, dendritic and myelin alterations, and glial activation, mainly in the hippocampus and prefrontal cortex. Biochemical and molecular changes included oxidative stress, pro-apoptotic signaling, inflammatory cytokine dysregulation, decreased neurotrophic support, and altered neurotransmitter dynamics. Age and sex influenced susceptibility, with juvenile or aged animals and females—particularly older females modeling breast cancer patients—showing greater deficits. Cumulative or repeated dosing exacerbated neurotoxicity, while single administrations produced milder, sometimes transient, impairments. Conclusions: Preclinical models provide compelling evidence that chemotherapeutic agents impair cognitive function via convergent mechanisms involving inflammation, oxidative stress, and synaptic dysregulation. These findings highlight the importance of considering age, sex, and treatment schedule in designing neuroprotective strategies and underscore the translational relevance of rodent models in understanding chemobrain. Full article
(This article belongs to the Special Issue Chemotherapy-Associated Brain Damage—Translational Insights from Pre-Clinical and Clinical Research)
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