Molecular mechanisms underlying cyclophosphamide-induced cognitive impairment and strategies for neuroprotection in preclinical models

Abstract

Cyclophosphamide has drastically enhanced the expectancy and quality of life of cancer patients. However, it is accompanied by diverse neurological complications which are considered a dose-limiting adverse effect. Neurotoxicity caused by cyclophosphamide can manifest in numerous manners including anxiety, depression, motor dysfunction and cognitive deficits. This review article offers an overview on cyclophosphamide-induced neurotoxicity, providing a unified point of view on the possible underlying molecular mechanisms including oxidative brain damage, neuroinflammation, apoptotic neuronal cell death as well as disruption of the balance of brain neurotransmitters and neurotrophic factors. Besides, this review sheds light on the promising protective agents that have been investigated using preclinical animal models as well as their biological targets and protection mechanisms. Despite promising results in experimental models, none of these agents has been studied in clinical trials. Thus, there is lack of evidence to advocate the use of any neuroprotective agent in the clinical setting. Furthermore, none of the protective agents has been evaluated for its effect on the anticancer activity of cyclophosphamide in tumor-bearing animals. Therefore, there is a great necessity for adequate well-designed clinical studies for evaluation of the therapeutic values of these candidates. Conclusively, this review summarizes the molecular mechanisms accounting for cyclophosphamide-induced neurotoxicity together with the potential protective strategies seeking for downgrading this neurological complication, thus enhancing the quality of life and well-being of cancer patients treated with cyclophosphamide.

Keywords: Cyclophosphamide; Molecular mechanisms; Neurotoxicity; Protective strategies.

Fig. 1

Cyclophosphamide-induced oxidative stress. ROS: Reactive oxygen species, MDA: Malondialdehyde, SOD: Superoxide dismutase, CAT: Catalase, GSH: Glutathione, GPx: Glutathione peroxidase, GR: Glutathione reductase

Fig. 2

Cyclophosphamide -induced downregulation of Nrf2 pathway. CUl3: Cullin 3, Keap1: Kelch-like ECH-associated protein 1, Nrf2: Nuclear factor erythroid 2-related factor 2

Fig. 3

Activation of NF-ΚB pathway by cyclophosphamide. IκB: Inhibitors of κB, IκK: IκB kinase

Fig. 4

Activation of TLR pathway by cyclophosphamide. TLRs: Toll-like receptors, Myd88: Myeloid differentiation primary response 88, TIRAP: toll-interleukin 1 receptor (TIR) domain-containing adaptor protein, TRAF-6: TNF receptor-associated factor 6, NFkB: Nuclear factor kappa B, Ap-1: activator protein 1, TRAM: Tumor associated macrophage, TRIF: TIR-domain-containing adapter-inducing interferon beta, IRF3: Interferon regulatory factor 3, IFNs: Interferons, IRAK: IL-1 receptor-associated kinase

Fig. 5

Activation of NLRP3 inflammasome/Caspase 1 signaling pathway by cyclophosphamide. NLRP3: the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3, IL-1β: Interleukin 1 beta, ASC: Apoptosis-associated speck-like protein

Fig. 6

Effect of cyclophosphamide on Sirt1/ NFkB axis

Fig. 7

The apoptotic pathway activation in cyclophosphamide neurotoxicity. FADD: Fas-associated death domain protein, TRADD: Tumor necrosis factor receptor type 1-associated DEATH domain protein, DISC: The death-inducing signalling complex, BID: The BH3 interacting-domain death agonist, BAX: Bcl-2-associated X protein, BCL-2: B-cell lymphoma 2, Apaf-1: Apoptotic protease activating factor-1

Fig. 8

The Mechanistic targets for neuroprotective approaches against cyclophosphamide-induced neurotoxicity