Plausible biochemical mechanisms of chemotherapy-induced cognitive impairment ("chemobrain"), a condition that significantly impairs the quality of life of many cancer survivors

Abstract

Increasing numbers of cancer patients survive and live longer than five years after therapy, but very often side effects of cancer treatment arise at same time. One of the side effects, chemotherapy-induced cognitive impairment (CICI), also called "chemobrain" or "chemofog" by patients, brings enormous challenges to cancer survivors following successful chemotherapeutic treatment. Decreased abilities of learning, memory, attention, executive function and processing speed in cancer survivors with CICI, are some of the challenges that greatly impair survivors' quality of life. The molecular mechanisms of CICI involve very complicated processes, which have been the subject of investigation over the past decades. Many mechanistic candidates have been studied including disruption of the blood-brain barrier (BBB), DNA damage, telomere shortening, oxidative stress and associated inflammatory response, gene polymorphism of neural repair, altered neurotransmission, and hormone changes. Oxidative stress is considered as a vital mechanism, since over 50% of FDA-approved anti-cancer drugs can generate reactive oxygen species (ROS) or reactive nitrogen species (RNS), which lead to neuronal death. In this review paper, we discuss these important candidate mechanisms, in particular oxidative stress and the cytokine, TNF-alpha and their potential roles in CICI.

Keywords: Blood-brain barrier; Chemotherapy-induced cognitive impairment; Mitochondrial dysfunction; Oxidative damage; TNF-alpha.

Fig 1.

Summary of candidate interrelated mechanisms of CICI discussed in this review paper.

Fig 2.

Proposed mechanisms of CICI mediated by ROS-generating chemotherapeutic drugs and associated oxidative stress. Such anti-cancer drugs in the periphery trigger oxidative stress and result in protein oxidation and lipid peroxidation, producing elevated TNF-αthat crosses the BBB by receptor-mediated endocytosis or by oxidative stress-mediated disruption of the BBB (see >>>>). TLR4 activation leads to BBB disruption and production of cytokines such as TNF-α. Once TNF-α goes into brain, local immune response is triggered by microglia activation and NF-κB activation, triggering ROS/RNS leading to oxidative stress. DNA repair systems are affected by the oxidative stress in brain and lead to neurodegeneration. Impaired mitochondria function follows the nitration of MnSOD and p53 non-transcriptional activation. As a result, mitochondria permeability transition pore (mPTP) is opened. Cyt c released from the pore initiates caspase signaling, leading to neural apoptosis. Once neurodegeneration and neuronal death happen, cognitive deficits of chemotherapy-treated cancer survivors appear.