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

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

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