Abstract
Chemotherapy can significantly prolong the survival of patients with breast cancer; Nevertheless, the majority of patients receiving chemotherapy such as doxorubicin may have cognitive deficits that manifest as impairments in learning, reasoning, attention, and memory. The phenomenon of chemotherapy-induced cognitive decline is termed as chemotherapy-related cognitive impairment (CRCI) or chemo-brain. Doxorubicin (DOX), a commonly used drug in adjuvant chemotherapy for patients with breast cancer, has been reported to induce chemo-brain through a variety of mechanisms including DNA damage, oxidative stress, inflammation, dysregulation of apoptosis and autophagy, changes in neurotransmitter levels, mitochondrial dysfunction, glial cell interactions, neurogenesis inhibition, and epigenetic factors. These mechanisms do not operate independently but are inter-related, coordinately contributing to the development of chemo-brain. Here we review the relationships of these mechanisms and pathways in attempt to provide mechanistic insights into the doxorubicin-induced cognitive impairment.
Highlights
It has been confirmed by a number of clinical as well as preclinical investigations that chemotherapy may cause cognitive impairment, and the mechanisms involved in the chemo-brain problem include DNA damage, oxidative stress, inflammatory responses, dysregulation of apoptosis and autophagy, altered neurotransmitter levels, aberration of some key kinases, mitochondrial dysfunction, glial cell interactions, inhibition of neurogenesis, and epigenetic factors
There is no specific treatment for chemotherapy-induced cognitive impairment, it has been reported that rehabilitation behavioral training, such as cognitive behavioral therapy (CBT), neuropsychological/ cognitive training intervention, physical activity, might improve the quality of life of the patients who suffer from chemo-brain
Because doxorubicin has limited ability to penetrate through the blood-brain barrier (BBB) and key factors in the induction of chemo-brain are oxidative stress and peripheral tumor necrosis factor-a (TNF-a) products, antioxidant or anti-inflammatory therapy often can significantly improves chemo-brain
Summary
It was generally believed that doxorubicin has a limited capacity to penetrate the blood-brain barrier and the brain is protected from its damage. Several studies have shown that doxorubicin has potential antitumor effects on brain cancer [14]. Clinical as well as animal studies have shown that doxorubicin was detected in the brain after peripheral administration of the drug [15, 16]. It was reported that doxorubicin could cross the blood-brain barrier through vascular-associated apical projections of neural stem cells (which are about 30 nm in diameter), can establish direct membrane-membrane contacts with the endothelial cells in specific regions of the irregular endothelial basement membrane, and have abundant vesicular activity [17]. The possible direct mechanisms of doxorubicin induced chemobrain are illustrated in Table 1 and Figure 1
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