Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy

Abstract

One consequence of modern cancer therapy is chemotherapy related cognitive dysfunction or "chemobrain", the subjective experience of cognitive deficits at any point during or following chemotherapy. Chemobrain, a well-established clinical syndrome, has become an increasing concern because the number of long-term cancer survivors is growing dramatically. There is strong evidence that correlates changes in peripheral cytokines with the development of chemobrain in commonly used chemotherapeutic drugs for different types of cancer. However, the mechanisms by which these cytokines elicit change in the central nervous system are still unclear. In this review, we hypothesize that the administration of chemotherapy agents initiates a cascade of biological changes, with short-lived alterations in the cytokine milieu inducing persistent epigenetic alterations. These epigenetic changes lead to changes in gene expression, alterations in metabolic activity and neuronal transmission that are responsible for generating the subjective experience of cognition. This speculative but testable hypothesis should help to gain a comprehensive understanding of the mechanism underlying cognitive dysfunction in cancer patients. Such knowledge is critical to identify pharmaceutical targets with the potential to prevent and treat cancer-treatment related cognitive dysfunction and similar disorders.

Keywords: Cancer chemotherapy; Chemobrain; Cognition dysfunction; Cytokines and epigenetics.

Fig. 1

Schematic representation of cytokine-mediated cascade associated with chemotherapy-induced cognitive dysfunction. Peripheral released cytokines can access the brain to initiate local release of cytokines (TNF-α, IL-1β, IL-6, and IFN-α) and chemokines (MCP-1) by following mechanisms: (1) passive crossing through the leaky regions in the blood–brain-barrier at circumventricular organs; (2) active transporting cross the blood–brain-barrier; (3) stimulating the HPA axis independently or synergistically by directly binding to the receptors expressed in the HPA axis or indirectly through affecting the secretion of ACTH from the hypothalamus, ACTH from the pituitary or glucocorticoids from the adrenal cortex; and (4) stimulation of endothelial cells and perivascular macrophages, monocytes and T cells in the brain to produce similar local cytokines/chemokines. To respond to the local released cytokines/chemokines, microglia, astrocytes, oligodendrocytes and neurons in the brain produce even more the similar types of cytokines/chemokines which in turn to influence neuronal neurotransmitters and integrity through (1) oxidative stress pathways to increase ROS and RNS (reactive oxygen and nitrogen species), which affect the synthesis of monoamines; (2) P38 MAPKs pathway to interfere with serotonin and dopamine transports (5-HTT/DAT) function; (3) affecting glutamate system by activation of IDO – QUIN – NMDAR/EAAT to lead to neuronal excitotoxicity; and finally (4) BDNF (brain derived neurotrophic factor) and TrkB pathway to negatively affect neurogenesis and neuroplasticity. All the pathways either working alone or synergistically contribute to the development of cognitive decline after chemotherapy exposure in cancer patients.

Fig. 2

Schematic illustration of epigenetic modulation and epigenetic therapeutic approaches for chemotherapy-induced cognitive dysfunction. Chemotherapy induced reprogramming of the epigenome, DNA methylation and histone modification, may be the plausible common pathway leading to persistent cognitive dysfunction after exposure of chemotherapeutic agents. Chemotherapeutic agents cause cytokine deregulation and may also directly induce epigenetic changes through DNA methylation and histone modification. Each of the factors, alone or synergistically, leads to changes in gene expression and cell proliferation in the brain, particularly in the hippocampal and prefrontal cortical areas, which may eventually lead to the manifestation of persistent cognitive dysfunction after chemotherapy. Therefore, therapeutic intervention (1) by tipping the balance of pro- and anti-inflammatory cytokines by acupuncture, (2) modification of DNA methylation by SAM and betaine, or histone acetylation by sirtuins, or (3) increasing neurotrophic factors, BDNF, level in the brain, might prove to be the therapeutic intervention of the future in psychoneurological symptoms induced by chemotherapy exposure.