The Route to \u2018Chemobrain\u2019 - Computational probing of neuronal LTP pathway

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

doi:10.1038/s41598-019-45883-9

Abstract

Chemotherapy causes deleterious side effects during the course of cancer management. The toxic effects may be extended to CNS chronically resulting in altered cognitive function like learning and memory. The present study follows a computational assessment of 64 chemotherapeutic drugs for their off-target interactions against the major proteins involved in neuronal long term potentiation pathway. The cancer chemo-drugs were subjected to induced fit docking followed by scoring alignment and drug-targets interaction analysis. The results were further probed by electrostatic potential computation and ligand binding affinity prediction of the top complexes. The study identified novel off-target interactions by Dactinomycin, Temsirolimus, and Everolimus against NMDA, AMPA, PKA and ERK2, while Irinotecan, Bromocriptine and Dasatinib were top interacting drugs for CaMKII. This study presents with basic foundational knowledge regarding potential chemotherapeutic interference in LTP pathway which may modulate neurotransmission and synaptic plasticity in patient receiving these chemotherapies.

Highlights

Therapies for cancer can cause both central and peripheral toxicities leading to a wide differential of cognitive changes which may span from acute onset delirium like symptoms to more progressive degenerative changes and delayed neurological consequences termed as ‘Chemobrain’,‘Chemofog’, ‘Cancer related Cognitive Impairment’ or ‘Chemotherapy induced Cognitive Impairment’ (CICI)[5,6,7,8,9,10]
And temporally, long term potentiation (LTP) can be dichotomized into Early LTP (E-LTP), which initiates following inducing stimulus lasting from few minutes to approx. 4 hours, and Late LTP (L-LTP) spanning from few hours to days, dependent on new protein synthesis[17]
Substantial evidence been put forwarded that CICI may be implicated to interfere LTP15,16.The investigative ground gets further complicated by considering the cancer patient specific clinico-pathological characteristic and the subsequent combination and dosage of chemotherapy administered[10]

Summary

Introduction

Therapies for cancer can cause both central and peripheral toxicities leading to a wide differential of cognitive changes which may span from acute onset delirium like symptoms to more progressive degenerative changes and delayed neurological consequences termed as ‘Chemobrain’,‘Chemofog’, ‘Cancer related Cognitive Impairment’ or ‘Chemotherapy induced Cognitive Impairment’ (CICI)[5,6,7,8,9,10]. Any off target interaction can interfere with NMDA-R transportation and re-sculpting neuronal synapse, thereby rejuvenating synaptic efficiency in general and E-LTP in particular. This resultantly, will affect L-LTP induction which is dependent on E-LTP. Alteration in their function leads to neural tube defects[23] They have been targeted for therapeutic modulation for CNS disorders like Schizophrenia[24], Depression[25], Alzheimer’s disease[26] and Epilepsy[27]. ‘off-target’ due to resemblances in protein binding topological state These off-target interactions can be a probable eventuality by considering the fact that drugs rarely binds to its only actual target[28]. If an off target is known to mediate a certain side effect, this information can be potentially utilized to adjust dose, avoid drug side effect and improve management in patients for better clinical outcomes

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