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  • BDNF is a neurotrophin widely


    BDNF is a neurotrophin widely expressed in CNS, mostly present in hippocampus and cerebral cortex. BDNF is involved in neuronal repair, dendritic and axonal growth, long-term potentiation and synaptic plasticity [127], associated with hippocampal volume reduction and memory function in aging processes [128]. Moreover, the BDNF Val66Met mutation has been shown to be associated with CICI and might be linked with cognitive depression associated with inflammation in breast cancer survivors [129,130]. In addition, this BDNF mutation has also been associated with lower hippocampal volume and poorer performance in measures of memory [[131], [132], [133]]. Early-stage breast cancer patients with BDNF Met allele who have received chemotherapy were more likely to be protected from CICI with better performance on verbal fluency and multitasking test, compared to those patients with a BDNF Val allele [134]. A longitudinal study also showed plasma BDNF levels were reduced after chemotherapy associated with self-reported cognitive impairment, however, no significant changes of plasma BDNF levels were observed after chemotherapy in patients with BDNF Met/Met genotype [135]. The COMT gene encodes the protein catechol-O-methyltransferase, an enzyme that catalyzes the O-methylation of the catecholamines (dopamine, epinephrine, and norepinephrine), regulating their degradation. Polymorphism of the COMT gene has been linked with cognitive impairment associated with chemotherapy. Dopamine is an important neurotransmitter involved in executive and memory function in the frontal cortex, and COMT is the main modulator of dopamine levels in this area (In PD, the substantia nigra pars compacta is the major Ezatiostat region demonstrating pathology). COMT gene polymorphisms have been associated with memory performance in normal aging and with different prefrontal function and structure [136]. In particular, the Val158Met polymorphism has been shown to affect neurotransmission, decreasing dopamine availability [137]. Furthermore, COMT polymorphism has been correlated with cognitive impairment in lymphocytic leukemia [138] and in adult breast cancer survivors [139]. In both cases, patients with the COMT-Val allele exhibited decreased performance in attention, motor speed, and verbal fluency when compared to patients with the COMT-Met allele.
    Changes of hormone levels after chemotherapy involved in CICI mechanisms Low levels of hormones, such as estrogen, progesterone and testosterone, influence cognitive function and have complicated neuroprotective and antioxidant effects as well as deleterious effects on cognition [[140], [141], [142], [143], [144], [145]]. Estrogen receptors are abundant in brain areas associated with memory and cognition [146]. Several studies show that these hormones, beside the neurotrophic and protective effects, are involved also in speech and memory functions [147]. Moreover, estrogen has a role in maintaining telomere lengths and it affects cognitive function by influencing the brain cholinergic system [148,149]. The physiological reduction of estrogen levels, associated with menopause in women, has been related to cognitive deficits, particularly in memory functioning [142]. This is relevant in the chemotherapy-induced cognitive impairment context because chemotherapy also can induce early menopause in women [150]. However, a cautionary note is apropos here: in a clinical trial of long-term estrogen alone or combined with progestin therapy for postmenopausal women, loss of cognitive function was observed [145]. In addition to the effects of chemotherapy, other adjuvant treatments, such as tamoxifen and aromatase inhibitors used in breast cancer or androgen ablation in prostate tumor, can lower levels of hormones [[151], [152], [153], [154]]. Inhibitors of enzymes involving estrogen generating or agents that block estrogen receptors are commonly used in treatment for breast cancer. Reportedly, verbal memory of breast cancer patients treated with anti-estrogen therapy was impaired [155]. Because of their role on cognitive function, the alteration of hormone levels after chemotherapy is considered as a plausible contributing factor in the mechanisms for development of CICI.