chemotherapy is one of the primary treatments for cancer . however , one of the most disturbing findings of recent studies of cancer survivors is the apparent prevalence of chemotherapy - associated adverse neurological effects , including vascular complications , seizures , mood disorders , cognitive dysfunctions , and peripheral neuropathies .
epidemiological studies have revealed chemotherapy - induced cognitive impairments and psychological distress in diverse types of cancer patients with peripheral tumors , including breast cancer , colorectal cancer , and lymphoma , as well as brain tumors such as glioma , glioblastoma , and primary central nervous system lymphoma . in addition , chemotherapy triggers changes in ion channels on dorsal root ganglia and dorsal horn neurons that generate secondary changes resulting in neuropathic pains .
there is clear evidence of the neurotoxicity of at least some forms of chemotherapy , although factors related to the use of specific diagnostic techniques and cancer treatments may also contribute to the side effects that have been identified . among various neurological side effects , cognitive impairment and mental depression
a number of factors may either protect against cognitive impairments or place individuals at an increased risk of impaired cognitive function .
these factors include the concomitant effects of the cancer and its treatment ( e.g. , medications , fatigue , depression , or anxiety ) , indirect and direct effects of chemotherapy ( e.g. , chemotherapy - induced anemia or menopause ) , factors particular to the individual patient ( e.g. , age , intelligence , educational level , or menopausal status ) .
thus , a number of factors complicate assessments of correlations between the side effects of chemotherapy and brain dysfunctions in patients , particularly memory deficits and mental depression . despite intensive efforts to manage the neurological side effects of chemotherapy in patients , and the development of chemoprotective agents
it is well established that the cytostatic effects of chemotherapeutic agents inhibit the process of cancer cell division .
chemotherapy may induce related changes , particularly in neurogenesis and synaptic plasticity , which are closely linked to the hippocampus .
the hippocampus is a major structure of the limbic system that has been studied extensively in individuals with difficulties in learning and memory and the regulation of emotions , which can be manifested in symptoms such as depression .
however , further studies on experimental animals are needed to verify these correlations . furthermore , epidemiological studies of cancer survivors exhibiting cognitive impairments are required to clarify the side effects of chemotherapeutic agents , and thus allow the development of new therapeutic agents without such side effects . recently
, various groups using experimental in vivo and in vitro models have reported that chemotherapy induces neurodegeneration and hippocampal dysfunctions , such as memory deficits ( table 1 ) .
this review provides an overview of in vivo and in vitro studies investigating the neurological effects of chemotherapeutic agents on the hippocampus and its functions , including cognition and depression , as well as the neurotoxicity of these agents .
summary of in vivo and in vitro studies evaluating the effects of various chemotherapeutic agents on behavioral dysfunctions and neurobiology
in the adult brain , progenitor / stem cells give rise to new neural cells in two active germinal zones called the subgranular zone in the dentate gyrus , which generates new granular cells in the adult hippocampus , and the forebrain subventricular zone , which gives rise to granular cells in the olfactory bulb .
the hippocampus is a limbic structure that plays a critical role in the formation and recovery of certain types of memory and the regulation of emotion , such as in depression .
new neurons in the adult hippocampus are derived from neural progenitor / stem cells located at the border between the hilus and granular cell layer of the dentate gyrus , a region called the subgranular zone , during the process of hippocampal neurogenesis .
factors such as age , genetics , excitatory input , ionizing radiation exposure , physiological stimuli , and environmental conditions regulate the rate of cell proliferation in the hippocampus , which in turn influences behavior . mental depression and cognitive impairment
may be due not only to changes in neurotransmitter concentrations and receptor activity levels but also to the impairment of brain plasticity , tissue remodeling , and alterations in adult hippocampal neurogenesis .
manipulations that decrease neurogenesis , such as radiation exposure , impair an animal s performance in hippocampal - dependent learning and memory tasks .
conversely , factors that increase neurogenesis , such as exercise , and improve hippocampal performance .
in addition , animal models of depression have also been reported to result in a decline in adult hippocampal neurogenesis , through either the proliferation of hippocampal progenitors or short - term survival of daughter cells .
thus , reduced rates of hippocampal neurogenesis lead to cognitive impairments and/or depression - like effects in experimental models .
therefore , neurotoxic agents affecting hippocampal neurogenesis may be useful tools to clarify the relationship between hippocampal neurogenesis and hippocampal dysfunction .
neuronal synaptic plasticity in the adult brain , which is closely linked with neurogenesis , is manifested at the cellular level by modifications in dendritic growth , axonal sprouting , synaptic remodeling , and the creation of new synapses .
hippocampal principal synapses are especially plastic , as they have been shown to be strengthened or weakened by activity .
the ability of a synapse to change the efficacy of its synaptic transmission , a process known as synaptic plasticity , is crucial to brain functions , and therefore , hippocampal plasticity plays an important role in hippocampal functions . in the mammalian brain , two of the best - characterized forms of synaptic transmission in the hippocampus are long - term potentiation and long - term depression , which have been identified as cellular substrates that are clearly related to learning and memory .
several studies have shown that neurotoxic agents and neurodegenerative diseases induce changes in synaptic plasticity and neurogenesis in the adult hippocampus .
therefore , further research on changes in plasticity - related signals under various conditions should provide a greater understanding of the specific relationships between plasticity and brain functions .
other limbic structures , including the amygdala , hypothalamus , and fornix , are also involved in cognition and emotional regulation .
the amygdala , mammillary body , and hypothalamus play pivotal roles in memory and mental depression .
in addition to the limbic system , the striatum and cortex are also thought to be associated with some types of memory .
the frontal and temporal cortices of the forebrain , the basal nuclei , and pituitary gland have been implicated in mental depression .
the structure and function of the hippocampus , which is closely associated with both cognition and emotional regulation , have been studied under various conditions .
therefore , this review will focus mainly on the detrimental effects of chemotherapy in the hippocampus of experimental animals .
chemotherapy is one of the primary treatments for cancer , and has been applied successfully to extend patients life spans .
however , there is increasing clinical interest in its adverse neurotoxic symptoms , including leukoencephalopathy , seizures , cerebral infarctions , and cognitive impairments .
there is now a growing body of evidence that cancer therapy - associated cognitive dysfunction occurs in many adults undergoing treatment for cancer and can not simply be attributed to stress , fatigue , or depression .
therefore , behavioral evaluations of hippocampal dysfunction induced by chemotherapy in experimental models are necessary to gain further insights into the genuine phenomena of chemotherapy - induced cognitive impairments and depression .
several studies using animal models have shown that various chemotherapeutic agents impair performance in one or more cognitive tests ( table 1 ) . however , the outcomes of tests of cognitive impairment after treatment with chemotherapeutic agents are highly dependent on the protocols used and the specific learning tasks applied . furthermore , some chemotherapy agents that can easily cross the blood - brain barrier ( e.g. , 5-fluorouracil and methotrexate ) directly or indirectly have detrimental effects on brain functions such as memory and depression .
however , several antineoplastic agents that do not cross blood - brain barrier ( e.g. , cyclophosphamide ) also affect cognitive functions .
hence , we do not yet mechanistically understand the effects of chemotherapy on cognition and emotional regulation .
to date , various groups have focused on the hippocampus , which has a critical role in memory processing , and they suggested that most cognitive deficits induced by chemotherapeutic agents in diverse paradigms are associated with the inhibition of hippocampal neurogenesis .
in addition , although the influence of chemotherapeutic agents on mood disorders has been less well studied than their effects on cognition , yang et al reported recently that methotrexate increases depression - like behaviors in mice both 1 and 7 days after treatment , which was related to reduced hippocampal neurogenesis and cell viability and increased cytotoxicity and apoptosis .
however , some studies have indicated that chemotherapeutic agents induce memory impairments and mood disorders , but do not affect hippocampal cell proliferation .
several possible pathways that may contribute to the neurotoxicity observed after chemotherapy in breast cancer patients have been elucidated , including indirect chemical toxicity and oxidative damage , direct neuronal injury , inflammation , or a type of autoimmune response .
inflammatory mechanisms within the central nervous system contribute to cognitive impairments through interactions between neurons and glial cells .
several agents , including cyclophosphamide and methotrexate , activate microglia in a manner that is characterized by thicker and longer processes and persistent activation , and these increased inflammatory responses may contribute to cognitive impairment .
folate is also critical to optimal cognitive function within the mature brain , neurotoxic amino acid metabolism , and neurotransmitter synthesis .
folate deficiency induced by methotrexate treatment is associated with mild cognitive dysfunction , depression , and a reduction in proliferating cells in the hippocampal dentate gyrus of adult mice .
in addition , chemotherapy - induced memory impairments are also involved in diverse factors including reductions of brain amine concentrations and increases in histone acetylation and apoptosis . moreover ,
chemotherapeutic agents ( e.g. , methotrexate ) affect synaptic plasticity - related signals , so such changes are associated with neuronal survival and plasticity - related cellular remodeling in the hippocampus .
thus , these factors may affect brain function , especially in the hippocampus , and thereby possibly impair cognition and induce depression .
in addition , tumor formation itself may affect hippocampal functions , possibly through inflammatory responses .
in murine cancer models , tumor formation induces depression - like behavior and memory deficits , and upregulates proinflammatory enzymes , including cyclooxygenase-2 and inducible nitric oxide synthase , in the hippocampus of tumor - bearing mice . in a mouse model of breast cancer
, methotrexate treatment further leads to mental depression and memory deficits and inhibition of hippocampal neurogenesis .
however , compared with tumor - free mice , tumor - bearing mice do exhibit a slight , non - significant decrease in hippocampal neurogenesis .
in addition to cognitive impairment and mental depression , alterations in consciousness , seizures , cerebral infarctions , paralysis , peripheral neuropathy , leukoencephalopathy , and ototoxicity are common and often dose - limiting complications of chemotherapy treatment .
these drugs induce such neurotoxicity via diverse mechanisms , including decreased hippocampal cell proliferation and hippocampal blood vessel density , cell death and neuronal degeneration , and the activation of microglia without changes in hippocampal cytokine levels in vivo .
additional studies of chemotherapy - induced neurotoxicity may assist in the development of strategies for ameliorating these serious side effects in cancer survivors .
the prevalence of neurotoxicity induced by chemotherapy markedly increases when the blood - brain barrier is either overwhelmed or bypassed .
several chemotherapeutic agents are used to treat brain tumors because they readily cross the blood - brain barrier ( e.g. , methotrexate , an antimetabolite and folic acid antagonist ; carmustine and lomustine , alkylating agents ; cisplatin , a heavy metal ; ifosfamide , an alkylating prodrug ) . as some chemotherapeutic drugs , including the anthracycline anticancer drug doxorubicin , do not cross the blood - brain barrier , several modified delivery systems have recently been developed to circumvent the limited access of such drugs to the brain , to allow these compounds to be used against brain tumors .
in addition to passage across the blood - brain barrier , other factors may contribute to the neurotoxicity of chemotherapy , including genetic predispositions , nutritional deficiencies , metabolic abnormalities , accompanying medications , depression , anxiety , or fatigue .
while there have been many in vivo studies associated with chemotherapy - induced memory deficits , there are complications in the direct extrapolation of specific data from in vivo studies .
this is because the damage seen in vivo following radiation exposure and other treatments affects not only neurons but also surrounding cells , such as glial and vascular endothelial cells .
therefore , to exclude these secondary effects of chemotherapy - induced damage to glial or vascular endothelial cells or neurons , it is important to clarify the precise negative effects of chemotherapy on neurons in vitro . despite intensive efforts to determine ways to successfully manage the neurological side effects of chemotherapy , and the development of chemoprotective agents , there is no generally accepted therapeutic protocol that precludes these untoward effects .
therefore , various studies have focused on identification and characterization of the mechanisms underlying chemotherapy - induced neurotoxicity .
although few studies have suggested that pretreatment with some chemotherapeutic agents ( e.g. , cyclophosphamide ) prevents neuronal cell death caused by serum deprivation , most research has shown that diverse chemotherapeutic agents have detrimental effects on neuronal cells due to the resultant changes in neuronal morphology .
furthermore , it has been reported that potential toxic effects in mature neuronal cells exposed to anticancer drugs can be alleviated through inhibition of the rho signaling pathway , the generation of neuronal nitric oxide synthase , and subsequent reactive oxygen species / reactive nitrogen species , as well as activation of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid / kainite receptors .
in addition , folate deficiency caused by chemotherapy induces abnormal tau phosphorylation and amyloid precursor protein upregulation , which can contribute to the pathogenesis of alzheimer s disease .
this indicates that folate deficiency is related to neurotoxicity , and its effects are comparable to the results of a previous in vivo study . moreover , excitotoxic mechanisms and caspase - mediated cell death contribute to the neurotoxicity of some compounds in mature neuronal cultures .
however , as mature neurons have stopped differentiating and are less sensitive than differentiating cells , further investigations related to chemotherapy - induced effects on immature neurons are required . in immature neurons
, methotrexate induces increases in cytotoxicity and reduction of cell viability by a caspase - dependent pathway .
the expression of active caspase-3 and caspase - specific poly(adp - ribose ) polymerase cleavage are increased markedly in immature neurons following methotrexate treatment , and the capspase-3 inhibitor , z - devd , significantly blocks the methotrexate - induced cytotoxicity , supporting the suggestion that the neurotoxicity of methotrexate in immature cells depends on the proapoptotic caspase pathway , particularly the caspase-3 related pathway . however , mature hippocampal neurons are resistant to the toxicity of methotrexate , suggesting that immature hippocampal cells are significantly more sensitive to methotrexate treatment than mature cells , and that the susceptibility of such hippocampal cells is consequentially dependent on cell differentiation . therefore , these in vitro systems may be useful in the study of the diverse neurotoxic effects of cancer chemotherapy .
despite the abundance of data regarding chemotherapy - induced neurotoxicity in cancer patients , there is still considerable uncertainty regarding the underlying mechanisms . moreover ,
many clinical studies are limited by diverse factors that complicate identification of the causes of such neurotoxic effects and resultant symptoms .
thus , there have been many cellular and molecular studies of chemotherapy - induced neurotoxicity , especially of cognitive impairment and mental depression , and its underlying mechanisms using experimental in vivo and in vitro approaches , such as animal behavioral tests .
studies using animal behavioral tests have demonstrated that treatment with various chemotherapeutic agents engenders memory deficits and depression , which have been linked to hippocampal neurogenesis .
several mechanisms of chemotherapy - induced neurotoxicity have been elucidated from in vivo models , including inflammatory responses and changes in levels of brain amines , folate , and histones .
however , it is difficult to determine which direct pathways are linked to chemotherapeutic - agent - induced neurotoxicity in vivo because of secondary effects of diverse factors , such as changes in glial cells and endothelial cells and various other factors . using in vitro approaches
, most anticancer drugs have been shown to induce morphological changes and various toxic effects in neurons through several pathways .
although far from complete , these investigations using in vivo and in vitro approaches are helpful in determining how best to further explore the causal mechanisms of chemotherapy - induced neurological side effects , and also in providing direction for the future development of optimized chemotherapeutic agents .
 there is accumulating clinical evidence that chemotherapeutic agents induce neurological side effects , including memory deficits and mood disorders , in cancer patients who have undergone chemotherapeutic treatments . 
 this review focuses on chemotherapy - induced neurodegeneration and hippocampal dysfunctions and related mechanisms as measured by in vivo and in vitro approaches . 
 these investigations are helpful in determining how best to further explore the causal mechanisms of chemotherapy - induced neurological side effects and in providing direction for the future development of novel optimized chemotherapeutic agents . 
INTRODUCTION
ROLES OF HIPPOCAMPAL NEUROGENESIS AND PLASTICITY IN HIPPOCAMPAL FUNCTIONS
CHEMOTHERAPY-INDUCED NEUROTOXICITY 
EFFECTS OF CHEMOTHERAPY ON NEURONS 
CONCLUSION