Doxorubicin induces dysregulation of AMPA receptor and impairs hippocampal synaptic plasticity leading to learning and memory deficits

Alhowail, Ahmad; Pinky, Priyanka D.; Eggert, Matthew; Bloemer, Jenna; Woodie, Lauren N.; Buabeid, Manal; Bhattacharya, Subhrajit; Jasper, Shanese L.; Bhattacharya, Dwipayan; Dhanasekaran, Muralikrishnan; Escobar, Martha; Arnold, Robert D.; Suppiramaniam, Vishnu

doi:10.1016/j.heliyon.2021.e07456

Cited by 11 publications

(8 citation statements)

References 90 publications

(115 reference statements)

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“…Both PL treatment and TAC treatment increased mRNA levels of Gria2, and TAC/PL had no effect on expression (Figure 8C). While we observed no changes in Gria1, increased levels of GluA2 have been reported to be associated with memory deficits after doxorubicin treatment [62]. In fact, GluA2 knockout mice displayed an increase in LTP [63], which agrees with our results.…”

Section: Discussionsupporting

confidence: 92%

Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment

Ntagwabira

Trujillo

McElroy

et al. 2022

IJMS

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Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient’s quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity.

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Section: Discussionsupporting

confidence: 92%

Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment

Ntagwabira

Trujillo

McElroy

et al. 2022

IJMS

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“…A literature review indicates that chemotherapeutic drugs can cause various adverse effects, including cardio‐vessel damage, hepatic toxicity, mucosal injury, inflammation, apoptosis, myotoxicity, dermal toxicity, nephrotoxicity, and cognitive impairment 16,17 . Our previous studies also confirmed the neurotoxicity associated with using the chemotherapeutic Doxorubicin 18,19 . However, there are very few reports on the direct effect of Doxorubicin and Cyclophosphamide on dopaminergic neurons currently.…”

Section: Introductionsupporting

confidence: 65%

“…16 , 17 Our previous studies also confirmed the neurotoxicity associated with using the chemotherapeutic Doxorubicin. 18 , 19 However, there are very few reports on the direct effect of Doxorubicin and Cyclophosphamide on dopaminergic neurons currently. Thus, the current research focused on assessing the effect of Doxorubicin and cyclophosphamide on dopaminergic neurons.…”

Section: Introductionmentioning

confidence: 99%

Evaluate the in vitro effect of anthracycline and alkylating cytophosphane chemotherapeutics on dopaminergic neurons

Desai,

Majrashi,

Pathak

et al. 2024

Cancer Reports

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BackgroundIatrogenesis is an inevitable global threat to healthcare that drastically increases morbidity and mortality. Cancer is a fatal pathological condition that affects people of different ages, sexes, and races around the world. In addition to the detrimental cancer pathology, one of the most common contraindications and challenges observed in cancer patients is severe adverse drug effects and hypersensitivity reactions induced by chemotherapy. Chemotherapy‐induced cognitive neurotoxicity is clinically referred to as Chemotherapy‐induced cognitive impairment (CICI), chemobrain, or chemofog. In addition to CICI, chemotherapy also causes neuropsychiatric issues, mental disorders, hyperarousal states, and movement disorders. A synergistic chemotherapy regimen of Doxorubicin (Anthracycline‐DOX) and Cyclophosphamide (Alkylating Cytophosphane‐CPS) is indicated for the management of various cancers (breast cancer, lymphoma, and leukemia). Nevertheless, there are limited research studies on Doxorubicin and Cyclophosphamide's pharmacodynamic and toxicological effects on dopaminergic neuronal function.AimThis study evaluated the dopaminergic neurotoxic effects of Doxorubicin and Cyclophosphamide.Methods and ResultsDoxorubicin and Cyclophosphamide were incubated with dopaminergic (N27) neurons. Neuronal viability was assessed using an MTT assay. The effect of Doxorubicin and Cyclophosphamide on various prooxidants, antioxidants, mitochondrial Complex‐I & IV activities, and BAX expression were evaluated by Spectroscopic, Fluorometric, and RT‐PCR methods, respectively. Prism‐V software (La Jolla, CA, USA) was used for statistical analysis. Chemotherapeutics dose‐dependently inhibited the proliferation of the dopaminergic neurons. The dopaminergic neurotoxic mechanism of Doxorubicin and Cyclophosphamide was attributed to a significant increase in prooxidants, a decrease in antioxidants, and augmented apoptosis without affecting mitochondrial function.ConclusionThis is one of the first reports that reveal Doxorubicin and Cyclophosphamide induce significant dopaminergic neurotoxicity. Thus, Chemotherapy‐induced adverse drug reaction issues substantially persist during and after treatment and sometimes never be completely resolved clinically. Consequently, failure to adopt adequate patient care measures for cancer patients treated with certain chemotherapeutics might substantially raise the incidence of numerous movement disorders.

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“…With regard to neuronal stimulation and memory formation, proteins facilitate signal transduction from receptors to activate different protein kinases [ 109 , 110 ]. These signaling pathways regulate the gene expression and protein synthesis required to modify ion channel properties and ion channel density in the synapses [ 111 , 112 , 113 ]. The expression of several proteins in the hippocampus is altered during hippocampal-dependent tasks, and these proteins include brain-derived neurotrophic factor (BDNF), calcium calmodulin dependent kinase II (CaMKII), extracellular regulated kinase ½ (ERK1/2), cAMP-response element binding protein (CREB), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and N-methyl- d -aspartate (NMDA) receptor [ 114 , 115 , 116 , 117 ].…”

Section: Effect Of Prenatal Alcohol Exposure On Protein Expression An...mentioning

confidence: 99%

“…Similarly, a reduction in CaMKII activity induces cognitive dysfunction. In addition, CaMKII activation can phosphorylate the AMPA-GluR1 subunit at the Ser 831 residue and lead to the mobilization of the GluR1 subunit to the synaptic membrane [ 113 ]. CaMKII also plays a critical role in LTP induction and maintenance [ 145 ].…”

Section: Effect Of Prenatal Alcohol Exposure On Protein Expression An...mentioning

confidence: 99%

Mechanisms Underlying Cognitive Impairment Induced by Prenatal Alcohol Exposure

Alhowail¹

2022

Brain Sciences

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Alcohol is one of the most commonly used illicit substances among pregnant women. Clinical and experimental studies have revealed that prenatal alcohol exposure affects fetal brain development and ultimately results in the persistent impairment of the offspring’s cognitive functions. Despite this, the rate of alcohol use among pregnant women has been progressively increasing. Various aspects of human and animal behavior, including learning and memory, are dependent on complex interactions between multiple mechanisms, such as receptor function, mitochondrial function, and protein kinase activation, which are especially vulnerable to alterations during the developmental period. Thus, the exploration of the mechanisms that are altered in response to prenatal alcohol exposure is necessary to develop an understanding of how homeostatic imbalance and various long-term neurobehavioral impairments manifest following alcohol abuse during pregnancy. There is evidence that prenatal alcohol exposure results in vast alterations in mechanisms such as long-term potentiation, mitochondrial function, and protein kinase activation in the brain of offspring. However, to the best of our knowledge, there are very few recent reviews that focus on the cognitive effects of prenatal alcohol exposure and the associated mechanisms. Therefore, in this review, we aim to provide a comprehensive summary of the recently reported alterations to various mechanisms following alcohol exposure during pregnancy, and to draw potential associations with behavioral changes in affected offspring.

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Doxorubicin induces dysregulation of AMPA receptor and impairs hippocampal synaptic plasticity leading to learning and memory deficits

Cited by 11 publications

References 90 publications

Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment

Piperlongumine as a Neuro-Protectant in Chemotherapy Induced Cognitive Impairment

Evaluate the in vitro effect of anthracycline and alkylating cytophosphane chemotherapeutics on dopaminergic neurons

Mechanisms Underlying Cognitive Impairment Induced by Prenatal Alcohol Exposure

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