Review Article Chemobrain: Chemotherapy-induced cognitive impairment Sindhu R1, Sri Harsha Chalasani2, Santhepete N. Manjula1* ABSTRACT The association between cancer chemotherapy and cognitive impairment is well recorded and much sought after. At times, the diagnosis of cancer itself may induce cognitive impairment. The stress experienced by cancer patients after diagnosis or during or after treatment may also result in cognitive impairment. The chemotherapy drugs themselves are stressors that cause adaptive signals and these could limit their clinical values. It is important to skim through the confounding factors and establish a stronger link between chemotherapy and cognitive impairment. This review article is aimed at evaluating the available information on cancer chemotherapy and cognitive impairment. KEY WORDS: Adverse drug reactions, Chemobrain, Chemotherapy, Cognitive impairment, Malignancy, Medication errors INTRODUCTION contribute to CICI, and this shows that further studies are required to characterize the role of CICI.[4,7] Since the 1970s, the studies relating cognitive variations The chemotherapy considered as a vulnerability for with cancer chemotherapy have been established, but the cognitive dysfunction and the degree of impairment may systematic reviews on the adverse cognitive outcomes be influenced by various treatments, and the pathway [1-3] of chemotherapy appeared only after the 1990s. excreted by these cytotoxic compounds.[8] The proof implicating the impact of chemotherapy on cognitive function over a decade has emerged from Single therapy is not sufficient to treat the cancer the neuropsychological studies of cancer survivors patients while the failure to respond to multiple and also from the longitudinal studies that include pre- drug therapy against chemotherapy adds further treatment neuropsychological assessments.[4] complications to the treatment.[9] The genotoxic stress response induced by anticancer agents is coupled with Chemobrain often referred to as chemofog or the additional stress response.[10,11] chemotherapy-induced cognitive impairment (CICI) is a common adverse effect in cancer patients In this review, we consider how stress affects receiving chemotherapy. Chemobrain refers to the cognitive impairment, and also this review has patients experiencing diverse cognitive changes that focused on how chemotherapy will induce stress and happen before or post-chemotherapy.[5] The common the relation between chemotherapy and cognitive manifestations include impairment in memory, difficulty impairment that is chemobrain. The brief periods of in word finding, decrease in executive function, stress that potentiate the formation of memory shown, difficulty in organizing tasks, and lower information and also the recent work has uncovered some of processing speed. Nearly 17–75% of cancer patients the mechanisms. The present review focuses on the receiving chemotherapy suffer from chemotherapy- pathways, vulnerability, assessment, and management mediated cognitive dysfunction.[6] The review of of cognitive dysfunction related to chemotherapy literature showed that in the United States, there are 15.5 drugs for cancer patients. The future areas of research million individuals who survived cancer and are likely to pursue are also high lightened in this review. facing long-term cognitive impairments due to cancer or its related treatments. Several hypothesized mechanisms EFFECT OF STRESS ON COGNITIVE FUNCTION Access this article online Cognition is affected by stress in many ways. Website: jprsolutions.info ISSN: 0975-7619 Stress affects cognition by acting rapidly through 1Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore, Karnataka, India, 2Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore, Karnataka, India *Corresponding author: Dr. Santhepete N. Manjula, Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysore - 570 015, Karnataka, India. Phone: +91-9916264940. E-mail: [email protected] Received on: 18-07-2019; Revised on: 20-08-2019; Accepted on: 26-09-2019 Drug Invention Today | Vol 11 • Special Issue 2 • 2019 199 Sindhu R, et al. catecholamines and more slowly through environment.[19] In solid tumors, the stress response glucocorticoids. The two types of stressors, such leads to the development of resistance to anticancer as physical and psychological stressors, elicit the drugs that act on tumor cells. This inability to respond production of catecholamines such as epinephrine can be reversed or deteriorated on amputation of and norepinephrine through the sympathetic stress conditions.[20] The stressful stimuli, along with nervous system, and the adrenal gland secretes anticancer drugs, cause overexpression of multidrug glucocorticoids.[12] The cognitive dysfunction resistance 1 gene that encodes with P-glycoprotein. occurs mainly due to change in the prefrontal cortex This encoding creates an ionic gradient that reduces activity. the accumulation of drugs in cancer cells which are regulated by heat shock protein (HSP) (heat-shock Catecholamines: Epinephrine and Norepinephrine factor 1).[21] The literature review has demonstrated that Ventral tegmental area and locus coeruleus are the hyperthermia, along with chemotherapy, induces anti- primary sources of epinephrine and norepinephrine, inflammatory stress response to modulate the action respectively, which respond to the prefrontal of anticancer drugs such as doxorubicin, cisplatin, cortex.[13] Overstimulation of dopamine that is bleomycin, mitomycin C, and teniposide.[22] The role of D1 receptor occurs due to stress which further each type of stress response and the individual degree activates cyclic adenosine monophosphate, causing of contribution to the resulting phenotype is hard to hyperpolarization of nucleotide-gated channels to allocate in the tumor environment. Thus, hyperthermia open. This results in shoving of incoming excitation. is allied with regional hypoxia, anticancer drugs, and In addition, activation of norepinephrine alpha-1 oxidative or metabolic stress may provoke genotoxic receptor initiates phospholipase C signaling series stress response through reactive oxygen species- that leads to loss of excitation through potassium dependent potentiation of the C-Jun-N-terminal and channel in the soma. This causes cognitive p38 mitogen-activated protein kinase pathways.[11] impairment.[14] Under stress condition, the lipase C releases norepinephrine throughout the brain, and in Besides, their direct interactions with DNA anticancer the prefrontal cortex, it binds to the alpha-1 receptor drugs elicit adverse effects by interfering with at lower affinity.[15] Activation of this receptor either stress response cascade.[23,24] The ribosomal protein pharmacologically or due to stress-induced release RPL36 and HSP 10 are responsible for resistance to of norepinephrine causes impairment in memory, chemotherapy drugs.[25] The overexpression of HSP70 cognitive impairment.[16] in breast cancer patients undergoing chemotherapy and a small increase in HSPs acts as an oxidative Glucocorticoids stressor.[23] In response to stress, many cochaperones Hypothalamic pituitary adrenal axis gets activated of HSP90 produce marked reallocation to the under stressful condition, which in turn causes nucleus.[26] However, only 17alpha-1 acid glycoprotein release glucocorticoids from the adrenal cortex. induces stress response on long-term treatment with These released glucocorticoids move through the chemotherapeutic agents.[27] bloodstream and cross the blood–brain barrier to trigger the glucocorticoid receptor in the brain, which CHEMOBRAIN causes memory impairment.[17] Chemobrain is also known as chemofog, or CICI Glucocorticoids interact with catecholamine by the refers to dysfunction of patients memory, learning, extraneuronal catecholamine transport system. These attention, speech, intellectual functioning, decision- carriers are present in the glia, which removes extra making, and visuospatial skills during the pre- or post- epinephrine and norepinephrine from the synapse chemotherapy.[28] Chemotherapy-related cognitive region. This keeps adrenergic and noradrenergic impairment is the most common adverse effects seen in receptor in balanced and optimum condition.[18] The cancer patients undergoing or after the discontinuation catecholamine transporters located in prefrontal cortex of chemotherapy.[29] inhibit the corticosterone, which result in the increase extracellular catecholamine levels. Thus, the stress- CICI Pathogenesis mediated glucocorticoid release causes stimulation of The exact pathogenesis of chemotherapy-induced both the dopamine 1 (D1) and alpha-1 noradrenergic cognitive function is unknown.[4] The etiology of receptor and causes cognitive impairment. CICI depends on the number of factors that lead to either direct or indirect effects on the central CHEMOTHERAPY-INDUCED nervous system, thus it in turn affects the cognitive STRESS capability of the cancer patients undergoing chemotherapy. The long-term cognitive impairment Experimental results support that anticancer in chemotherapy-treated individuals who have cancer drugs induce a stress response in the tumor is determined by genetic predisposition. The studies 200 Drug Invention Today | Vol 11 • Special Issue 2 • 2019 Sindhu R, et al. have shown that the cancer patients having allele CICI as explained in