The Route to ‘Chemobrain’ - Computational probing of neuronal LTP pathway

Fahim, Ammad; Rehman, Zaira; Bhatti, Muhammad Faraz; Virk, Nasar; Ali, Amjad; Rashid, Amir; Paracha, Rehan Zafar

doi:10.1038/s41598-019-45883-9

Cited by 7 publications

(3 citation statements)

References 170 publications

(135 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The neurological process of learning and memory depends upon synaptic plasticity, and larger synaptic efficiency is involved in the form of LTP. So, the inappropriate loss of synaptic activity or the abnormalities in the induction and maintenance of LTP may result in cognitive impairment (Fahim et al 2019).…”

Section: Oxidative Stressmentioning

confidence: 99%

Animal models of chemotherapy-induced cognitive decline in preclinical drug development

et al. 2021

View full text Add to dashboard Cite

Rationale Chemotherapy-induced cognitive impairment (CICI), chemobrain, and chemofog are the common terms for mental dysfunction in a cancer patient/survivor under the influence of chemotherapeutics. CICI is manifested as short/long term memory problems and delayed mental processing, which interferes with a person’s day-to-day activities. Understanding CICI mechanisms help in developing therapeutic interventions that may alleviate the disease condition. Animal models facilitate critical evaluation to elucidate the underlying mechanisms and form an integral part of verifying different treatment hypotheses and strategies. Objectives A methodical evaluation of scientific literature is required to understand cognitive changes associated with the use of chemotherapeutic agents in different preclinical studies. This review mainly emphasizes animal models developed with various chemotherapeutic agents individually and in combination, with their proposed mechanisms contributing to the cognitive dysfunction. This review also points toward the analysis of chemobrain in healthy animals to understand the mechanism of interventions in absence of tumor and in tumor-bearing animals to mimic human cancer conditions to screen potential drug candidates against chemobrain. Results Substantial memory deficit as a result of commonly used chemotherapeutic agents was evidenced in healthy and tumor-bearing animals. Spatial and episodic cognitive impairments, alterations in neurotrophins, oxidative and inflammatory markers, and changes in long-term potentiation were commonly observed changes in different animal models irrespective of the chemotherapeutic agent. Conclusion Dyscognition exists as one of the serious side effects of cancer chemotherapy. Due to differing mechanisms of chemotherapeutic agents with differing tendencies to alter behavioral and biochemical parameters, chemotherapy may present a significant risk in resulting memory impairments in healthy as well as tumor-bearing animals.

show abstract

Section: Oxidative Stressmentioning

confidence: 99%

Animal models of chemotherapy-induced cognitive decline in preclinical drug development

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In this work, we did not take into account other microenvironmental factors for CRCC in anti-cancer therapy such as signaling networks [ 86 ], neurogenesis and gliogenesis [ 66 ], biochemical interactions between cells such as microglia, neuron, and astrocytes [ 66 ], neuroimmune axes dynamics [ 52 , 66 ] in the presence of the Blood-Brain Barriers [ 87 ]. A multi-scale mathematical model [ 5 , 6 , 48 , 88 – 94 ] can be used to incorporate inter- and intra-cellular signaling at the microscale level and integrating biochemical and biomechanical mechanism of stromal cells and cancer cells at the cellular level.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies

Lee

Kim

2021

PLoS Comput Biol

View full text Add to dashboard Cite

Acute administration of trastuzumab (TZB) may induce various forms of cognitive impairment. These cancer-related cognitive changes (CRCC) are regulated by an adverse biological process involving cancer stem cells (CSCs) and IL-6. Recent studies have reported that atorvastatin (ATV) may change the dynamic of cognitive impairment in a combination (TZB+ATV) therapy. In this study, we investigate the mutual interactions between cancer stem cells and the tumor cells that facilitate cognitive impairment during long term TZB therapy by developing a mathematical model that involves IL-6 and the key apoptotic regulation. These include the densities of tumor cells and CSCs, and the concentrations of intracellular signaling molecules (NFκB, Bcl-2, BAX). We apply the mathematical model to a single or combination (ATV+TZB) therapy used in the experiments to demonstrate that the CSCs can enhance CRCC by secreting IL-6 and ATV may interfere the whole regulation. We show that the model can both reproduce the major experimental observation on onset and prevention of CRCC, and suggest several important predictions to guide future experiments with the goal of the development of new anti-tumor and anti-CRCC strategies. Moreover, using this model, we investigate the fundamental mechanism of onset of cognitive impairment in TZB-treated patients and the impact of alternating therapies on the anti-tumor efficacy and intracellular response to different treatment schedules.

show abstract

“…Those changes are most likely related to the ability of chemotherapeutics to interact off-target with: N-methyl- D -aspartate receptor (NMDA-R), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPA-R), protein kinase A (PKA), extracellular signal-regulated kinase (ERK2), and Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), which are major regulators of LTP. The effect on LTP was pointed as possible for several drugs, including dactinomycin and irinotecan in in silico simulation ( Fahim et al, 2019 ). However, impairment of LTP was also observed in rodent models due to cisplatin and DOX treatment ( Mu et al, 2015 ; Alhowail et al, 2019 ).…”

Section: Central Neurotoxicity: Chemobrainmentioning

confidence: 99%

Mechanisms of Chemotherapy-Induced Neurotoxicity

et al. 2022

View full text Add to dashboard Cite

Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients’ quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients’ quality of life.

show abstract

The Route to ‘Chemobrain’ - Computational probing of neuronal LTP pathway

Cited by 7 publications

References 170 publications

Animal models of chemotherapy-induced cognitive decline in preclinical drug development

Animal models of chemotherapy-induced cognitive decline in preclinical drug development

Atorvastatin-mediated rescue of cancer-related cognitive changes in combined anticancer therapies

Mechanisms of Chemotherapy-Induced Neurotoxicity

Contact Info

Product

Resources

About