Kemobeyin Tanı ve Tedavi Yaklaşımları

Yıl 2025, Cilt: 17 Sayı: 2, 301 - 322

Fatma Gül Helvacı Çelik , Meltem Puşuroğlu , Sefanur Köse , Çiçek Hocaoğlu

https://doi.org/10.18863/pgy.1503639

Öz

Gelişen kanser tedavileri ve artan tedavi sonrası yaşam süreleriyle birlikte, kanser tedavisinin yol açtığı sorunlar daha belirgin hale gelmiştir. Kemoterapi gibi birçok tedavi, sistemik olarak uygulanmakta olup bu da ciddi sistemik yan etkilere neden olmaktadır. Kanser tedavisi sürecinde ve sonrasında, bilişsel kayıplar ortaya çıkabilir. Bu kayıplar, yürütücü işlevlerde bozulma, dikkat ve hafıza sorunları, kelime bulma güçlüğü ve yeni beceriler edinememe gibi belirtilerle kendini gösterebilir. Bu durum, "kemobeyin" olarak adlandırılmaktadır. Kemoterapi sonrası bilişsel bozulma yüksek oranlarda gözlemlenebilir ve bazı durumlarda uzun süreli olabilir. Bu da yaşam kalitesinde düşüşe ve işlevsellik kaybına neden olabilir. Kemobeyin patofizyolojisi üzerine öne sürülen mekanizmalar arasında, kan-beyin bariyeri bütünlüğünün bozulmasıyla geçirgenliğin ve beyin hassasiyetinin artması, deoksiriboz nükleik asit (DNA) hasarı ve buna bağlı DNA onarımı eksiklikleri, telomer kısalması, oksidatif stres, proinflamatuar sitokinler ve nöroinflamasyon-nörotoksisite, nöronal genetik yatkınlık ve epigenetik değişiklikler, kemoterapi sonrası hormonal değişiklikler, reaktif oksijen radikalleri ve etkileri, spinal ve dentritik arborizasyon kaybı, mikrotübül disentegrasyonu, azalmış nörogenesis, nörotransmitter değişiklikleri, mitokondrial disfonksiyon ve spinal dansite kaybı yer almaktadır. Bu derleme, güncel literatür bilgileri eşliğinde kemobeyin özellikleri, klinik belirtileri, patofizyolojisi ve kemobeyini önlemeye ya da tedavisine yönelik seçeneklerin değerlendirilmesini amaçlamaktadır.

Anahtar Kelimeler

kemoterapi, kemobeyin, tanı, tedavi, bilişsel işlevler

Destekleyen Kurum

yok

Teşekkür

yok

Diagnostic and Treatment Approaches to Chemo Brain

Öz

Advancements in cancer treatment and the consequent increase in post-treatment survival have brought the challenges associated with cancer therapy into sharper focus. Many treatment modalities, such as chemotherapy, are administered systemically, leading to significant systemic side effects. Cognitive impairments, including deficits in executive functions, attention, memory, word finding difficulties, and the inability to acquire new skills, can arise during and after cancer treatment, a phenomenon known as "chemo brain." Post-chemotherapy cognitive impairment can be observed at high rates and may persist long-term in nearly one-third of cases, resulting in a decline in quality of life and functional impairment. Proposed mechanisms underlying the pathophysiology of chemo brain include disruption of blood-brain barrier integrity leading to increased permeability and brain susceptibility, DNA damage and associated deficiencies in DNA repair, telomere shortening, oxidative stress, pro-inflammatory cytokines and neuroinflammation-neurotoxicity, neuronal genetic susceptibility and epigenetic changes, post-chemotherapy hormonal alterations, reactive oxygen radicals and effects, loss of spinal and dendritic arborization, microtubule disintegration, reduced neurogenesis, neurotransmitter alterations, mitochondrial dysfunction, and loss of spinal density. This review aims to evaluate the characteristics, clinical manifestations, pathophysiology, and options for prevention or treatment of chemo brain, accompanied by current literature findings, thereby contributing to the existing body of knowledge.

Anahtar Kelimeler

Kemobeyin, kemoterapi, bilişsel işlevller, tanı, tedavi

Kaynakça

• Abd El-Aal SA, AbdElrahman M, Reda AM, Afify H, Ragab GM, El-Gazar AA et al. (2022) Galangin mitigates DOX-induced cognitive impairment in rats: Implication of NOX-1/Nrf-2/HMGB1/TLR4 and TNF-α/MAPKs/RIPK/MLKL/BDNF. Neurotoxicology, 92:77-90.
• Abdollahzadeh M, Panahpour H, Ghaheri S, Saadati H (2022) Calcitriol supplementation attenuates cisplatin-induced behavioral and cognitive impairments through up-regulation of BDNF in male rats. Brain Res Bull, 181:21-29.
• Abulizi A, Ran J, Ye Y, An Y, Zhang Y, Huang Z et al. (2021) Ganoderic acid improves 5-fluorouracil-induced cognitive dysfunction in mice. Food Funct, 12:12325-12337.
• Acharya MM, Martirosian V, Chmielewski NN, Hanna N, Tran KK, Liao AC et al. (2015) Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction. Cancer Res, 75: 676 – 686.
• Ahles TA, Saykin AJ (2002) Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer, 3:84-90.
• Ahles TA, Saykin AJ (2007) Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer, 7:192-201.
• Alexander JF, Mahalingam R, Seua AV, Wu S, Arroyo LD, Hörbelt T et al.(2022) Targeting the meningeal compartment to resolve chemobrain and neuropathy via nasal delivery of functionalized mitochondria. Adv Healthc Mater, 11:e2102153.
• Alexander JF, Seua AV, Arroyo LD, Ray PR, Wangzhou A, Heiβ-Lückemann L et al. (2021) Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics, 11:3109-3130.
• Alharbi I, Alharbi H, Almogbel Y, Alalwan A, Alhowail A (2020) Effect of metformin on doxorubicin-induced memory dysfunction. Brain Sci, 10:152.
• Alhowail AH (2024) Pioglitazone ameliorates DOX-induced cognitive impairment by mitigating inflammation, oxidative stress, and apoptosis of hippocampal neurons in rats. Behav Brain Res, 457:114714.
• Ali MA, Menze ET, Tadros MG, Tolba MF (2020) Caffeic acid phenethyl ester counteracts doxorubicin-induced chemobrain in Sprague-Dawley rats: Emphasis on the modulation of oxidative stress and neuroinflammation. Neuropharmacology, 181:108334.
• Ali AE, Elsherbiny DM, Azab SS, El-Demerdash E (2022) The diuretic amiloride attenuates doxorubicin-induced chemobrain in rats: Behavioral and mechanistic study. Neurotoxicology, 88:1-13.
• Altarifi AA, Sawali K, Alzoubi KH, Saleh T, Abu Al-Rub M, Khabour O (2024) Effect of vitamin E on doxorubicin and paclitaxel-induced memory impairments in male rats. Cancer Chemother Pharmacol, 93:215-224.
• Alsaud MM, Alhowail AH, Aldubayan MA, Almami IS (2023) The ameliorative effect of pioglitazone against neuroinflammation caused by doxorubicin in rats. Molecules, 28:4775.
• Alsikhan RS, Aldubayan MA, Almami IS, Alhowail AH (2023) Protective effect of galantamine against doxorubicin-induced neurotoxicity. Brain Sci, 13:971.
• Alvarez J, Meyer FL, Granoff DL, Lundy A (2013) The effect of EEG biofeedback on reducing postcancer cognitive impairment. Integr Cancer Ther, 12:475-487.
• Andres AL, Gong X, Di K, Bota DA (2014) Low-doses of cisplatin injure hippocampal synapses: a mechanism for ‘chemo’ brain?. Exp Neurol, 255:137–144.
• Arvanitis CD, Ferraro GB, Jain RK (2020) The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer, 20:26-41.
• Butterfield DA (2014) The 2013 SFRBM discovery award: selected discoveries from the butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment. Free Radic Biol Med, 74:157-174.
• Bray VJ, Dhillon HM, Bell ML, Kabourakis M, Fiero MH, Yip D et al. (2017) Evaluation of a web-based cognitive rehabilitation program in cancer survivors reporting cognitive symptoms after chemotherapy. J Clin Oncol, 35:217-225.
• Callaghan CK, O'Mara SM (2015) Long-term cognitive dysfunction in the rat following docetaxel treatment is ameliorated by the phosphodiesterase-4 inhibitor, rolipram. Behav Brain Res, 290:84-89.
• Campbell KL, Zadravec K, Bland KA, Chesley E, Wolf F, Janelsins MC (2020) The effect of exercise on cancer-related cognitive impairment and applications for physical therapy: Systematic review of randomized controlled trials. Phys Ther, 100:523-542.
• Chang A, Chung NC, Lawther AJ, Ziegler AI, Shackleford DM, Sloan EK et al. (2020) The anti-inflammatory drug aspirin does not protect against chemotherapy-induced memory impairment by paclitaxel in mice. Front Oncol, 10:564965.
• Chaturvedi RK, Flint Beal M (2013) Mitochondrial diseases of the brain. Free Radic Biol Med, 63:1-29.
• Cheng H, Li W, Gan C, Zhang B, Jia Q, Wang K (2016) The COMT (rs165599) gene polymorphism contributes to chemotherapy-induced cognitive impairment in breast cancer patients. Am J Transl Res, 8: 5087 – 5097.
• Cheung YT, Ng T, Shwe M, Ho HK, Foo KM, Cham MT et al. (2015) Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study. Ann Oncol, 26: 1446-1451.
• Chiang ACA, Seua AV, Singhmar P, Arroyo LD, Mahalingam R, Hu J et al. (2020) Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice. Acta Neuropathol Commun, 8:193.
• Cheruku SP, Ramalingayya GV, Chamallamudi MR, Biswas S, Nandakumar K, Nampoothiri M et al. (2018) Catechin ameliorates doxorubicin-induced neuronal cytotoxicity in in vitro and episodic memory deficit in in vivo in Wistar rats. Cytotechnology, 70:245-259.
• Chen J, Wang J, Li C, Ding H, Ye J, Xia Z (2021) Dexmedetomidine reverses MTX-induced neurotoxicity and inflammation in hippocampal HT22 cell lines via NCOA4-mediated ferritinophagy. Aging, 13:6182-6193.
• Chen Y, Sheng J, Tang X, Zhao Y, Zhu S, Liu Q (2022) Clemastine rescues chemotherapy-induced cognitive impairment by improving white matter integrity. Neuroscience, 484:66-79.
• Chaturvedi RK, Flint Beal M (2013) Mitochondrial diseases of the brain. Free Radic Biol Med, 63:1-29.
• Chiu GS, Boukelmoune N, Chiang ACA, Peng B, Rao V, Kingsley C et al. (2018) Nasal administration of mesenchymal stem cells restores cisplatin-induced cognitive impairment and brain damage in mice. Oncotarget, 9:35581-35597.
• Chtourou Y, Gargouri B, Kebieche M, Fetoui H (2015) Naringin abrogates cisplatin-induced cognitive deficits and cholinergic dysfunction through the down-regulation of AChE expression and iNOS signaling pathways in hippocampus of aged rats. Mol Neurosci, 56:349- 362.
• Dickerman JD (2007) The late effects of childhood cancer therapy. Pediatrics, 119:554-568.
• Ding H, Xiang R, Jia Y, Ye J, Xia Z (2023) Cyclosporin A-mediated translocation of HuR improves MTX-induced cognitive impairment in a mouse model via NCOA4-mediated ferritinophagy. Aging, 15:12537-12550.
• Dizon DS, Kamal AH (2024) Cancer statistics 2024: All hands on deck. CA Cancer J Clin, 74: 8-9.
• Dooley LN, Ganz PA, Cole SW, Crespi CM, Bower JE (2016) Val66Met BDNF polymorphism as a vulnerability factor for inflammation-associated depressive symptoms in women with breast cancer. J Affect Disord, 197: 43-50.
• Du J, Zhang A, Li J, Liu X, Wu S, Wang B et al. (2021) Doxorubicin-induced cognitive impairment: the mechanistic insights. Front Oncol, 11: 673340.
• Edwardson DW, Boudreau J, Mapletoft J, Lanner C, Kovala AT, Parissenti AM (2017) Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance. PloS one, 12: e0183662.
• El-Agamy SE, Abdel-Aziz AK, Wahdan S, Esmat A, Azab SS (2018) Astaxanthin ameliorates doxorubicin-induced cognitive impairment (Chemobrain) in experimental rat model: impact on oxidative, inflammatory, and apoptotic machineries. Mol Neurobiol, 55: 5727 – 5740.
• El-Agamy SE, Abdel-Aziz AK, Esmat A, Azab SS (2019) Chemotherapy and cognition: comprehensive review on doxorubicin-induced chemobrain. Cancer Chemother Pharmacol, 84:1-14.
• Elbeltagy M, Al-Horani RA, Alsharaeh TS, Alkhatib AH, Alawaisheh I, Abuhani AA et al. (2024) The counter effect of exercise on cisplatin-induced cognitive and proliferation impairments. Cureus, 16:e52526.
• Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, McLaren M et al. (2010) Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci, 30: 5368-5375.
• Fardell JE, Vardy J, Shah JD, Johnston IN (2012) Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity. Psychopharmacology, 220:183-193.
• Fernandes HA, Richard NM, Edelstein K (2019) Cognitive rehabilitation for cancer-related cognitive dysfunction: a systematic review. Support Care Cancer, 27:3253-3279.
• Forrest MP, Parnell E, Penzes P (2018) Dendritic structural plasticity and neuropsychiatric disease. Nat Rev Neurosci, 19: 215 – 234
• Gan H, Zhang Q, Zhu B, Wu S, Chai D (2019) Fluoxetine reverses brain radiation and temozolomide-induced anxiety and spatial learning and memory defect in mice. J Neurophysiol, 121:298-305.
• Gaman AM, Uzoni A, Popa-Wagner A, Andrei A, Petcu EB (2016) The role of oxidative stress in etiopathogenesis of chemotherapy induced cognitive impairment (CICI)-“Chemobrain”. Aging Dis, 7:307.
• Groves TR, Farris R, Anderson JE, Alexander TC, Kiffer F, Carter G et al. (2017) 5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice. Behav Brain Res, 316: 215 –224.
• Gutmann DH (2019) Clearing the fog surrounding chemobrain. Cell, 176:2-4.
• Haller OJ, Semendric I, George RP, Collins-Praino LE, Whittaker AL (2023) The effectiveness of anti-inflammatory agents in reducing chemotherapy-induced cognitive impairment in preclinical models - A systematic review. Neurosci Biobehav Rev, 148:105120.
• Heim C, Binder EB (2012) Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene–environment interactions, and epigenetics. Exp Neurol, 233: 102-111.
• Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med, 361:1475 – 1485
• Ho KH (2015) Insights into the mechanism of'chemobrain': deriving a multi-factorial model of pathogenesis. Australian Medical Student Journal, 6(1).
• Huehnchen P, Bangemann N, Lischewski S, Märschenz S, Paul F, Schmitz-Hübsch T et al. (2022) Rationale and design of the prevention of paclitaxel-related neurological side effects with lithium trial - Protocol of a multicenter, randomized, double-blind, placebo- controlled proof-of-concept phase-2 clinical trial. Front Med, 9:967964.
• Hutchinson AD, Hosking JR, Kichenadasse G, Mattiske JK, Wilson C (2012) Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer Treat Rev, 38: 926-934.
• Hurria A, Somlo G, Ahles T (2007) Renaming "chemobrain". Cancer Invest, 25:373-377.
• Hussien M, Yousef MI (2022) Impact of ginseng on neurotoxicity induced by cisplatin in rats. Environmental science and pollution research international. Environ Sci Pollut Res Int, 29:62042-62054.
• Ibrahim SS, Abo Elseoud OG, Mohamedy MH, Amer MM, Mohamed YY, Elmansy SA et al. (2021) Nose-to-brain delivery of chrysin transfersomal and composite vesicles in doxorubicin-induced cognitive impairment in rats: Insights on formulation, oxidative stress and TLR4/NF-kB/NLRP3 pathways. Neuropharmacology, 197:108738.
• Inagaki M, Yoshikawa E, Matsuoka Y, Sugawara Y, Nakano T, Akechi T et al. (2007) Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer, 109:146-156.
• Isaac MFG, Alkhatib R, Ho CL (2024) MRI characteristics of chemotherapy-related central neurotoxicity: a pictorial review. Insights Imaging, 15:12.
• Jia L, Zhou Y, Ma L, Li W, Chan C, Zhang S et al. (2023) Inhibition of NLRP3 alleviated chemotherapy-induced cognitive impairment in rats. Neurosci Lett, 793:136975.
• Jiang ZG, Winocur G, Wojtowicz JM, Shevtsova O, Fuller S, Ghanbari HA (2018) PAN-811 prevents chemotherapy-induced cognitive impairment and preserves neurogenesis in the hippocampus of adult rats. PloS one, 13:e0191866.
• Janelsins MC, Heckler CE, Peppone LJ, Kamen C, Mustian KM, Mohile SG et al. (2017) Cognitive complaints in survivors of breast cancer after chemotherapy compared with age-matched controls: An analysis from a nationwide, multicenter, prospective longitudinal study. J Clin Oncol, 35:506-514.
• Jarmolowicz DP, Gehringer R, Lemley SM, Sofis MJ, Kaplan S, Johnson MA (2019) 5-Fluorouracil impairs attention and dopamine release in rats. Behav Brain Res, 362: 319 – 322.
• Johnston IN, Tan M, Cao J, Matsos A, Forrest DRL, Si E et al.(2017) Ibudilast reduces oxaliplatin-induced tactile allodynia and cognitive impairments in rats. Behav Brain Res, 334:109-118.
• Juan Z, Chen J, Ding B, Yongping L, Liu K, Wang L et al. (2022) Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial. Eur J Cancer, 161:10-22.
• Kang S, Lee S, Kim J, Kim JC, Kim SH, Son Y et al. (2018) Chronic treatment with combined chemotherapeutic agents affects hippocampal micromorphometry and function in mice, independently of neuroinflammation. Exp Neurobiol, 27: 419 – 436.
• Kaplan SV, Limbocker RA, Gehringer RC, Divis JL, Osterhaus GL, Newby MD et al. (2016) Impaired brain dopamine and serotonin release and uptake in Wistar rats following treatment with carboplatin. ACS Chem Neurosci, 7: 689 – 699.
• Keeney JTR, Ren X, Warrier G, Noel T, Powell DK, Brelsfoard JM et al. (2018) Doxorubicin-induced elevated oxidative stress and neurochemical alterations in brain and cognitive decline: protection by MESNA and insights into mechanisms of chemotherapy-induced cognitive impairment (“chemobrain”). Oncotarget, 9: 30324 – 30339.
• Keeney JT, Swomley AM, Förster S, Harris JL, Sultana R, Butterfield DA (2013) Apolipoprotein A-I: insights from redox proteomics for its role in neurodegeneration. Proteomics Clin Appl, 7:109-122.
• Khalil HMA, El Henafy HMA, Khalil IA, Bakr AF, Fahmy MI, Younis NS et al. (2023) Hypericum perforatum L. nanoemulsion mitigates cisplatin-induced chemobrain via reducing neurobehavioral alterations, oxidative stress, neuroinflammation, and apoptosis in adult tats. Toxics, 11:159.
• Khodabakhsh P, Asgari Taei A, Shafaroodi H, Pournajaf S, Dargahi L (2024) Effect of metformin on epidermal neural crest stem cells and their potential application in ameliorating paclitaxel-induced neurotoxicity phenotype. Stem Cell Rev Rep, 20:394-412.
• Khuanjing T, Maneechote C, Ongnok B, Prathumsap N, Arinno A, Chunchai T et al. (2023) Acetylcholinesterase inhibition protects against trastuzumab-induced cardiotoxicity through reducing multiple programmed cell death pathways. Mol Med, 129:123.
• Kim T, James BT, Kahn MC, Blanco-Duque C, Abdurrob F, Islam MR et al. (2024) Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice. Sci Transl Med, 16:eadf4601.
• Kitamura Y, Ushio S, Sumiyoshi Y, Wada Y, Miyazaki I, Asanuma M et al. (2021) N-acetylcysteine attenuates the anxiety-like behavior and spatial cognition impairment induced by doxorubicin and cyclophosphamide combination treatment in rats. Pharmacology, 106:286-293.
• Koffie RM, Hashimoto T, Tai HC, Kay KR, Serrano-Pozo A, Joyner D et al. (2012) Apolipoprotein E4 effects in Alzheimer’s disease are mediated by synaptotoxic oligomeric amyloid-β. Brain, 135: 2155-2168.
• Kohli S, Fisher SG, Tra Y, Adams MJ, Mapstone ME, Wesnes KA et al. (2009) The effect of modafinil on cognitive function in breast cancer survivors. Cancer, 115:2605-2616.
• Kovalchuk A, Ilnytskyy Y, Rodriguez-Juarez R, Katz A, Sidransky D, Kolb B et al. (2017) Growth of malignant extracranial tumors alters microRNAome in the prefrontal cortex of Tumor Graft mice. Oncotarget, 8:88276–88293.
• Kuo PH, Chen AY, Rodriguez RJ, Stuehm C, Chalasani P, Chen NK et al. (2023) Transcranial magnetic stimulation for the treatment of chemo brain. Sensors, 23:8017.
• Lal R, Dharavath RN, Chopra K (2023) Alpha-lipoic acid ameliorates doxorubicin-induced cognitive impairments by modulating neuroinflammation and oxidative stress via NRF-2/HO-1 signaling pathway in the rat hippocampus. Neurochem Res, 48:2476-2489.
• Lawrence JA, Griffin L, Balcueva EP, Groteluschen DL, Samuel TA, Lesser GJ et al. (2016) A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy. J Cancer Surviv, 10:176-184.
• Lee J, Kim JS, Kim Y (2021) Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies. PLoS Comput Biol, 17:e1009457.
• Li X-J, Dai ZY, Zhu BY, Zhen JP, Yang WF, Li DQ et al. (2014) Effects of sertraline on executive function and quality of life in patients with advanced cancer. Med Sci Monit, 20:1267.
• Li C, Niu J, Zhou B, Deng W, Deng F, Zhou Z et al. (2020) Dexmedetomidine attenuates cisplatin-induced cognitive impairment by modulating miR-429-3p expression in rats. 3 Biotech, 10:244.
• Lim I, Joung HY, Yu AR, Shim I, Kim JS (2016) PET evidence of the effect of donepezil on cognitive performance in an animal model of chemobrain. Biomed Res Int, 2016: 6945415.
• Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev, 46:3-26.
• Lu JIA, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res, 43:348-364.
• Lyons L, ElBeltagy M, Umka J, Markwick R, Startin C, Bennett G et al. (2011) Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy. Psychopharmacology, 215:105-115.
• Lyons L, ElBeltagy M, Bennett G, Wigmore P (2012) Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery. PloS one, 7:e30010.
• Lyu W, Ouyang M, Ma X, Han T, Pi D, Qiu S (2021) Kai-Xin-San attenuates doxorubicin-induced cognitive impairment by reducing inflammation, oxidative stress, and neural degeneration in 4T1 breast cancer mice. Evid Based Complement Alternat Med, 2021: 5521739.
• Ma J, Huo X, Jarpe MB, Kavelaars A, Heijnen CJ (2018) Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment. Acta Neuropathol Commun, 6:103.
• Manchon JFM, Uzor NE, Kesler SR, Wefel JS, Townley DM, Nagaraja AS et al. (2016) TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin. Aging (Albany NY), 8:3507.
• Mahmoud AMA, Mantawy EM, Wahdan SA, Ammar RM, El-Demerdash E (2023) Vildagliptin restores cognitive function and mitigates hippocampal neuronal apoptosis in cisplatin-induced chemo-brain: Imperative roles of AMPK/Akt/CREB/ BDNF signaling cascades. Biomed Pharmacother, 159:114238
• Mani V, Rabbani SI, Shariq A, Amirthalingam P, Arfeen M (2022) Piracetam as a therapeutic agent for doxorubicin-induced cognitive deficits by enhancing cholinergic functions and reducing neuronal inflammation, apoptosis, and oxidative stress in rats. Pharmaceuticals, 15:1563.
• Mani V, Arfeen M, Rabbani SI, Shariq A, Amirthalingam P (2022) Levetiracetam ameliorates doxorubicin-induced chemobrain by enhancing cholinergic transmission and reducing neuroinflammation using an experimental rat model and molecular docking study. Molecules, 27:7364.
• Mar Fan HG, Clemons M, Xu W, Chemerynsky I, Breunis H, Braganza S et al.(2008) A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Cancer, 16:577-583.
• Marín AP, Sánchez AR, Arranz EE, Auñón PZ, Barón MG (2009) Adjuvant chemotherapy for breast cancer and cognitive impairment. South Med J, 102: 929-934
• Maynard S, Fang EF, Scheibye-Knudsen M, Croteau DL, Bohr VA (2015) DNA damage, DNA repair, aging, and neurodegeneration. Cold Spring Harb Perspect Med, 5: a025130.
• Moretti RL, Dias EN, Kiel SG, Augusto MCM, Rodrigues PS, Sampaio ACS et al. (2021) Behavioral and morphological effects of resveratrol and curcumin in rats submitted to doxorubicin-induced cognitive impairment. Res Vet Sci, 140:242-245.
• Morid OF, Menze ET, Tadros MG, George MY (2023) L-carnitine modulates cognitive impairment induced by doxorubicin and cyclophosphamide in rats; insights to oxidative stress, inflammation, synaptic plasticity, liver/brain, and kidney/brain Axes. J Neuroimmune Pharmacol, 18:310-326.
• Moruno-Manchon JF, Uzor NE, Kesler SR, Wefel S, Townley DM, Nagaraja AS et al. (2016) TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin. Aging, 8:3507-3519.
• Mounier NM, Wahdan SA, Gad AM, Azab SS (2021) Role of inflammatory, oxidative, and ER stress signaling in the neuroprotective effect of atorvastatin against doxorubicin-induced cognitive impairment in rats. Naunyn Schmiedebergs Arch Pharmacol, 394:1537-1551.
• Nguyen LD, Ehrlich BE (2020) Cellular mechanisms and treatments for chemobrain: insight from aging and neurodegenerative diseases. EMBO Mol Med, 12:e12075.
• Ongnok B, Khuanjing T, Chunchai T, Pantiya P, Kerdphoo S, Arunsak B et al. (2021) Donepezil protects against doxorubicin-induced chemobrain in rats via attenuation of inflammation and oxidative stress without interfering with doxorubicin efficacy. Neurotherapeutics, 18:2107-2125.
• Ongnok B, Prathumsap N, Chunchai T, Pantiya P, Arunsak B, Chattipakorn N et al. (2024) Nicotinic and muscarinic acetylcholine receptor agonists counteract cognitive impairment in a rat model of doxorubicin-induced chemobrain via attenuation of multiple programmed cell death pathways. Mol Neurobiol, Published online April 3.
• Oliveros A, Yoo KH, Rashid MA, Corujo-Ramirez A, Hur B, Sung J et al.(2022) Adenosine A(2A) receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function. Proc Natl Acad Sci U S A, 119:e2206415119.
• Park JH, Jung YS, Kim KS, Bae SH (2017) Effects of compensatory cognitive training intervention for breast cancer patients undergoing chemotherapy: a pilot study. Support Care Cancer, 25:1887-1896
• Park HS, Kim CJ, Kwak HB, No MH, Heo JW, Kim TW (2018) Physical exercise prevents cognitive impairment by enhancing hippocampal neuroplasticity and mitochondrial function in doxorubicin-induced chemobrain. Neuropharmacology, 133:451-461.
• Park SH, Ko JR, Han J (2024) Exercise alleviates cisplatin-induced toxicity in the hippocampus of mice by inhibiting neuroinflammation and improving synaptic plasticity. Korean J Physiol Pharmacol, 28:145-152.
• Philpot RM, Ficken M, Johns BE, Engberg ME, Wecker L (2019) Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors. Cancer Chemother Pharmacol, 84: 579-589.
• Piña-Sánchez P, Chávez-González A, Ruiz-Tachiquín M, Vadillo E, Monroy-García A, Montesinos JJ et al. (2021) Cancer biology, epidemiology, and treatment in the 21st Century: current status and future challenges from a biomedical perspective. Cancer Control, 28:10732748211038735.
• Pondugula SR, Majrashi M, Almaghrabi M, Ramesh S, Abbott KL, Govindarajulu M et al. (2021) Oroxylum Indicum ameliorates chemotherapy induced cognitive impairment. PloS one, 16:e0252522.
• Popa-Wagner A, Mitran S, Sivanesan S, Chang E, Buga AM (2013). ROS and brain diseases: the good, the bad, and the ugly. Oxid Med Cell Longev, 2013:963520.
• Pun PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res, 43:348-364.
• Raafat RS, Habib MZ, Abdelfattah AA, Olama NK, Abdelraouf SM, Hendawy N et al.(2023) Amisulpride attenuates 5-fluorouracil-induced cognitive deficits via modulating hippocampal Wnt/GSK-3β/β-catenin signaling in Wistar rats. Immunopharmacol, 124:110945.
• Rao V, Bhushan R, Kumari P, Cheruku SP, Ravichandiran V, Kumar N (2022) Chemobrain: A review on mechanistic insight, targets and treatments. Adv Cancer Res, 155:29-76.
• Ramalingayya GV, Cheruku SP, Nayak PG, Kishore A, Shenoy R, Rao CM et al.(2017) Rutin protects against neuronal damage in vitro and ameliorates doxorubicin-induced memory deficits in vivo in Wistar rats. Drug Des Devel Ther, 11:1011-1026.
• Rashid MA, Oliveros A, Kim YS, Jang MH (2022) Nicotinamide mononucleotide prevents cisplatin-induced mitochondrial defects in cortical neurons derived from human induced pluripotent stem cells. Brain Plast, 8:143-152.
• Rashid MA, Tang JJ, Yoo KH, Corujo-Ramirez A, Oliveros A, Kim SH et al.(2023) The selective cyclooxygenase-2 inhibitor NS398 ameliorates cisplatin-induced impairments in mitochondrial and cognitive function. Front Mol Neurosci, 16:1295991.
• Reis AS, Paltian JJ, Domingues WB, Costa GP, Alves D, Giongo JL et al. (2020) Pharmacological modulation of Na(+), K(+)-ATPase as a potential target for OXA-induced neurotoxicity: Correlation between anxiety and cognitive decline and beneficial effects of 7-chloro-4-(phenylselanyl) quinoline. Brain Res Bull, 162: 282-290.
• Ren X, Boriero D, Chaiswing L, Bondada S, St Clair DK, Butterfield DA (2019) Plausible biochemical mechanisms of chemotherapy-induced cognitive impairment ("chemobrain"), a condition that significantly impairs the quality of life of many cancer survivors. Biochim Biophys Acta Mol Basis Dis, 1865:1088-1097.
• Saadati H, Noroozzadeh S, Esmaeili H, Amirshahrokhi K, Shadman J, Niapour A (2021) The neuroprotective effect of mesna on cisplatin-induced neurotoxicity: behavioral, electrophysiological, and molecular studies. Neurotox Res, 39:826-840.
• Savitz J, Solms M, Ramesar R (2006) The molecular genetics of cognition: dopamine, COMT and BDNF. Genes Brain Behav, 5: 311-328.
• Seigers R, Timmermans J, van der Horn HJ, de Vries EF, Dierckx RA, Visser L et al. (2010) Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release. Behav Brain Res, 207: 265 – 272.
• Shaker FH, El-Derany MO, Wahdan SA, El-Demerdash E, El-Mesallamy HO (2021) Berberine ameliorates doxorubicin-induced cognitive impairment (chemobrain) in rats. Life Sci, 269:119078.
• Sharma S, Raj K, Singh S (2022) Protective effects of cerebrolysin against chemotherapy (carmustine) induced cognitive impairment in Albino mice. Drug Chem Toxicol, 45:2769-2779.
• Sheldrick AJ, Krug A, Markov V, Leube D, Michel TM, Zerres K et al. (2008) Effect of COMT val158met genotype on cognition and personality. Eur Psychiatry, 23: 385 – 389.
• Shi DD, Dong CM, Ho LC, Lam CTW, Zhou XD, Wu EX et al. (2018) Resveratrol, a natural polyphenol, prevents chemotherapy-induced cognitive impairment: Involvement of cytokine modulation and neuroprotection. Neurobiol Dis, 114:164-173.
• Shi DD, Huang YH, Lai CSW, Dong CM, Ho LC, Li XY et al.(2019) Ginsenoside Rg1 prevents chemotherapy-induced cognitive impairment: Associations with microglia-mediated cytokines, neuroinflammation, and neuroplasticity. Mol Neurobiol, 56:5626-5642.
• Shukla D, Kaur S, Singh A, Narang RK, Singh C (2024) Enhanced antichemobrain activity of amino acid assisted ferulic acid solid dispersion in adult zebrafish (Danio rerio). Drug Deliv Transl Res, Published online April 4.
• Silberfarb PM (1983) Chemotherapy and cognitive defects in cancer patients. Annu Rev Med, 34:35-46.
• Singh AK, Mahalingam R, Squillace S, Jacobson KA, Tosh DK, Dharmaraj S et al. (2022) Targeting the A(3) adenosine receptor to prevent and reverse chemotherapy-induced neurotoxicities in mice. Acta Neuropathol Commun, 10:11.
• Simó M, Rifà-Ros X, Rodriguez-Fornells A, Bruna J (2013) Chemobrain: a systematic review of structural and functional neuroimaging studies. Neurosci Biobehav Rev, 37:1311-1321.
• Sioka C, Kyritsis AP (2009) Central and peripheral nervous system toxicity of common chemotherapeutic agents. Cancer Chemother Pharmacol, 63:761-767.
• Small BJ, Rawson KS, Walsh E, Jim HS, Hughes TF, Iser L et al. (2011) Catechol-O-methyltransferase genotype modulates cancer treatment-related cognitive deficits in breast cancer survivors. Cancer, 117: 1369 – 1376.
• Sofis MJ, Jarmolowicz DP, Kaplan SV, Gehringer RC, Lemley SM, Garg G et al.(2017) KU32 prevents 5-fluorouracil induced cognitive impairment. Behav Brain Res, 329:186-190.
• Sung PS, Chen PW, Yen CJ, Shen MR, Chen CH, Tsai KJ et al.(2021) Memantine protects against paclitaxel-induced cognitive impairment through modulation of neurogenesis and inflammation in mice. Cancers,13:4177.
• Taillibert S, Le Rhun E, Chamberlain MC (2016) Chemotherapy-related neurotoxicity. Curr Neurol Neurosci Rep, 16:81.
• Tan CJ, Lim SWT, Toh YL, Ng T, Yeo A, Shwe M et al. (2019). Replication and meta-analysis of the association between BDNF Val66Met polymorphism and cognitive impairment in patients receiving chemotherapy. Mol Neurobiol, 56:4741-4750.
• Tangpong J, Cole MP, Sultana R, Joshi G, Estus S, Vore M et al. (2006) Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity. Neurobiol Dis, 23:127-139.
• Tangpong J, Cole MP, Sultana R, Joshi G, Estus S, Vore M et al. (2007) Adriamycin-mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain. J Neurochem, 100:191-201.
• Tanimukai H, Kudo T(2015) Fluvoxamine alleviates paclitaxel-induced neurotoxicity. Biochem Biophys Rep, 4: 202-206.
• Tesi EP, Ben-Azu B, Mega OO, Mordi J, Knowledge OO, Awele ED et al. (2022) Kolaviron, a flavonoid-rich extract ameliorates busulfan-induced chemo-brain and testicular damage in male rats through inhibition of oxidative stress, inflammatory, and apoptotic pathways. J Food Biochem, 46:e14071.
• Thomas TC, Beitchman JA, Pomerleau F, Noel T, Jungsuwadee P, Butterfield DA et al. (2017) Acute treatment with doxorubicin affects glutamate neurotransmission in the mouse frontal cortex and hippocampus. Brain Res, 1672: 10–17.
• Tong Y, Wang K, Sheng S, Cui J. (2020) Polydatin ameliorates chemotherapy-induced cognitive impairment (chemobrain) by inhibiting oxidative stress, inflammatory response, and apoptosis in rats. Biosci Biotechnol Biochem, 84:1201-1210.
• Usmani MT, Krattli RP Jr, El-Khatib SM, Le ACD, Smith SM, Baulch JE et al. (2023) BDNF augmentation using riluzole reverses doxorubicin-induced decline in cognitive function and neurogenesis.. Neurotherapeutics, 20: 909.
• Valko M, Jomova K, Rhodes CJ, Kuča K, Musílek K (2015) Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol, 90:1-37.
• Vaure C, Liu Y (2014) A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol, 5:316.
• Vega JN, Albert KM, Mayer IA, Taylor WD, Newhouse PA (2019) Nicotinic treatment of post-chemotherapy subjective cognitive impairment: a pilot studyi J Cancer Surviv, 13:673-686.
• Verstappen CC, Heimans JJ, Hoekman K, Postma TJ (2003) Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs, 63:1549-1563.
• Wahdan SA, El-Derany MO, Abdel-Maged AE, Azab SS (2020) Abrogating doxorubicin-induced chemobrain by immunomodulators IFN-beta 1a or infliximab: Insights to neuroimmune mechanistic hallmarks. Neurochem Int, 138:104777.
• Wang XM, Walitt B, Saligan L, Tiwari AF, Cheung CW, Zhang ZJ (2015) Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. Cytokine,72: 86 – 96.
• Wang D, Wang B, Liu Y, Dong X, Su Y, Li S (2019) Protective effects of ACY-1215 against chemotherapy-related cognitive impairment and brain damage in mice. Neurochem Res, 44:2460-2469
• Wang C, Zhao Y, Wang L, Pan S, Liu Y, Li S et al.(2021) C-phycocyanin mitigates cognitive impairment in doxorubicin-induced chemobrain: Impact on neuroinflammation, oxidative stress, and brain mitochondrial and synaptic alterations. Neurochem Res, 46:149-158.
• Walker AK, Chang A, Ziegler AI, Dhillon HM, Vardy JL, Sloan EK (2018) Low dose aspirin blocks breast cancer-induced cognitive impairment in mice. PloS one, 13:e0208593.
• Wardill HR, Mander KA, Van Sebille YZ, Gibson RJ, Logan JM, Bowen MJ et al.(2016a) Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. Int J Cancer, 139:2635-2645.
• Wardill HR, Gibson RJ, Van Sebille YZ, Secombe KR, Coller JK, White IA et al. (2016b) Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mechanisms. Mol Cancer Ther, 15:1376-1386.
• Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA (2004) The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer, 100:2292-2299.
• Wefel JS, Saleeba AK, Buzdar AU, Meyers CA (2010) Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer, 116:3348-3356.
• Wefel JS, Schagen SB (2012) Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep, 12:267-275.
• Wei T, Wang L, Tang J, Ashaolu TJ, Olatunji OJ (2022) Protective effect of Juglanin against doxorubicin-induced cognitive impairment in rats: Effect on oxidative, inflammatory and apoptotic machineries. Metab Brain Dis, 37:1185-1195.
• Whittaker AL, George RP, O'Malley L (2022) Prevalence of cognitive impairment following chemotherapy treatment for breast cancer: a systematic review and meta-analysis. Sci Rep, 12:2135.
• Winocur G, Binns MA, Tannock I (2011) Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology, 61:1222-1228.
• Winocur G (2017) Chemotherapy and cognitive impairment: An animal model approach. Can J Exp Psychol, 71:265-273.
• Yağmurlu B, Akyürek S, Fitöz S, Demirkazık A (2008) Malign bozuklukların neoplastik olmayan kraniyal komplikasyonlarının manyetik rezonans görüntülemesi. Diagn Interv Radiol, 14:61-68.
• Yang M, Moon C (2013) Neurotoxicity of cancer chemotherapy. Neural Regen Res, 8:1606-1614.
• Yao S, Zhu Q, Zhang Q, Cai Y, Liu S, Pang L et al.(2023) Managing Cancer and Living Meaningfully (CALM) alleviates chemotherapy related cognitive impairment (CRCI) in breast cancer survivors: A pilot study based on resting-state fMRI. Cancer Med, 12:16231-16242.
• Yi LT, Dong SQ, Wang SS, Chen M, Li CF, Geng D et al. (2024) Curcumin attenuates cognitive impairment by enhancing autophagy in chemotherapy. Neurobiol Dis, 194:106480.
• Yoshikawa E, Matsuoka Y, Inagaki M, Nakano T, Akechi T, Kobayakawa M et al. (2005) No adverse effects of adjuvant chemotherapy on hippocampal volume in Japanese breast cancer survivors. Breast Cancer Res Treat, 92:81-84.
• Yoo KH, Tang JJ, Rashid MA, Cho CH, Corujo-Ramirez A, Choi J et al. (2021) Nicotinamide mononucleotide prevents cisplatin-induced cognitive impairments. Cancer Res, 81:3727-3737.
• Zhou W, Kavelaars A, Heijnen CJ (2016) Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PloS One, 11:e0151890.
• Zhou X, Zhang X, Zhong T, Zhou M, Gao L, Chen L (2024) Prevalence and associated factors of chemotherapy-related cognitive impairment in older breast cancer survivors. J Adv Nurs, 80:484-499.