Cellular mechanisms and treatments for chemobrain: insight from aging and neurodegenerative diseases

Abstract

Chemotherapy is a life-saving treatment for cancer patients, but also causes long-term cognitive impairment, or "chemobrain", in survivors. However, several challenges, including imprecise diagnosis criteria, multiple confounding factors, and unclear and heterogeneous molecular mechanisms, impede effective investigation of preventions and treatments for chemobrain. With the rapid increase in the number of cancer survivors, chemobrain is an urgent but unmet clinical need. Here, we leverage the extensive knowledge in various fields of neuroscience to gain insights into the mechanisms for chemobrain. We start by outlining why the post-mitotic adult brain is particularly vulnerable to chemotherapy. Next, through drawing comparisons with normal aging, Alzheimer's disease, and traumatic brain injury, we identify universal cellular mechanisms that may underlie the cognitive deficits in chemobrain. We further identify existing neurological drugs targeting these cellular mechanisms that can be repurposed as treatments for chemobrain, some of which were already shown to be effective in animal models. Finally, we briefly describe future steps to further advance our understanding of chemobrain and facilitate the development of effective preventions and treatments.Cognitive complaints are common among cancer patients during and after chemotherapy. Cross-sectional and longitudinal studies suggest that short-term memory, working memory, and verbal ability are most frequently affected, followed by visuospatial memory, executive functions, and attention span (for meta-analyses, see

Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy

“…Another important aspect highlighted by preclinical studies is the involvement of the central nervous system in OIPN [21,22]. However, most of the studies regarding the central effects of neurotoxic chemotherapy are only focused on cognitive impairment ("chemofog" or "chemobrain") [61][62][63], while very little attention has been paid so far to this important aspect, particularly regarding the painful component of OIPN. It is, therefore, advisable that this lack of information will be addressed by well-conducted clinical studies profiting from the possibility to investigate the central nervous system at the functional level with magnetic resonance imaging or to modulate its activity using transcranial stimulation because this approach might open the way to new therapeutic attempts [64].…”

Long‐COVID syndrome‐associated brain fog and chemofog: Luteolin to the rescue

“…55,56 A number of drugs have been implicated in "chemobrain" (Table 2) most notably doxorubicin, [57][58][59] methotrexate, 60,61 lenalidomide, 62 rituximab, 62 and trastuzamab. 63 There have been intense efforts to understand the biochemical 64 or cellular 44,65,66 mechanisms responsible for chemobrain. These have included disrupted neurogenesis, 67 aberrant myelination, 6869 interference with prefrontal activity, 70 but most importantly neuroinflammation 66 with cytokine dysregulation.…”

“…63 There have been intense efforts to understand the biochemical 64 or cellular 44,65,66 mechanisms responsible for chemobrain. These have included disrupted neurogenesis, 67 aberrant myelination, 6869 interference with prefrontal activity, 70 but most importantly neuroinflammation 66 with cytokine dysregulation. 69,71 T A B L E 1 Symptoms present in long-COVID syndrome…”

Cancer Chemotherapy Related Cognitive Impairment and the Impact of the Alzheimer’s Disease Risk Factor APOE

“…While the increasing success in treating cancer improves survivorship, the detrimental effects of cancer chemotherapy on the central nervous system (CNS), including neurotoxicity and reduced cognitive ability, have been observed for decades [ 1 , 2 , 3 , 4 , 5 ]. Cancer related cognitive impairments (CRCI) affect memory, verbal ability, and executive functions [ 6 , 7 ]. Mitigating the CNS side effects would substantially improve prognoses by increasing quality of life [ 8 , 9 , 10 , 11 ].…”