Abrogating doxorubicin-induced chemobrain by immunomodulators IFN-beta 1a or infliximab: Insights to neuroimmune mechanistic hallmarks

Highlights

• IFN or Infliximab halted doxorubicin-induced memory processing abnormalities.

• IFN or Infliximab precluded doxorubicin-induced hippocampal neurodegeneration.

• IFN or Infliximab exerted antioxidant, anti-inflammatory and anti-apoptotic activities.

Abstract

Chemobrain is a well-established clinical syndrome that impairs patient's daily function, in particular attentiveness, coordination and multi-tasking. Thus, it interferes with patient's quality of life. The putative pharmacological intervention against chemobrain relies on understanding the molecular mechanisms underlying it. This study aimed to examine the potential neuroprotective effects of two immunomodulators: Interferon-β-1a (IFN-β-1a), as well as Tumor necrosis function-alpha (TNF-α) inhibitor; Infliximab in doxorubicin (DOX)-induced chemobrain in rats. Besides, the current study targets investigating the possible molecular mechanisms in terms of neuromodulation and interference with different death routes controlling neural homeostasis. Herein, the two immunomodulators IFN-β-1a at a dose of 300,000 units; s.c.three times per week, or Infliximab at a dose of 5 mg/kg/week; i.p. once per week were examined against DOX (2 mg/kg/w, i.p.) once per week for 4 consecutive weeks in rats.The consequent behavioral tests and markers for cognitive impairment, oxidative stress, neuroinflammation, apoptosis and neurobiological abnormalities were further evaluated. Briefly, IFN-β-1a or Infliximab significantly protected against DOX-induced chemobrain. IFN-β-1a or Infliximab ameliorated DOX-induced hippocampal histopathological neurodegenerative changes, halted DOX-induced cognitive impairment, abrogated DOX-induced mitochondrial oxidative, inflammatory and apoptotic stress, mitigated DOX-induced autophagic dysfunction and finally upregulated the mitophagic machineries. In conclusion, these findings suggest that either IFN-β-1a or Infliximab offers neuroprotection against DOX-induced chemobrain which could be explained by their antioxidant, anti-inflammatory, pro-autophagic, pro-mitophagic and antiapoptotic effects. Future clinical studies are recommended to personalize either use of IFN-β-1a or infliximab to ameliorate DOX-induced chemobrain.

Introduction

Although researches took remarkable successful steps in treatment path, cancer treatment remains a doubled-edged sword with rising hazardous side effects on non-cancerous tissues. One of these, is the post-chemotherapy related cognitive dysfunction, commonly referred to as “chemobrain” or “chemofog” (Ahles et al., 2012). Chemobrain is a well-established clinical syndrome that impairs patient's daily function, in particular attentiveness, concentration, coordination and multi-tasking (Hutchinson et al., 2012). These impairments interfere with the patient's quality of life as they reportedly persist several years posttreatment (de Ruiter et al., 2011). Doxorubicin (DOX), a topoisomerase interactive agent commonly used in treatment of several types of solid tumors including breast cancer, is increasingly associated with cognitive side effects (El-Agamy et al., 2018; Keeney et al., 2018; Volkova and Russell, 2011).

Successful pharmacological interventions against chemotherapy-induced cognitive dysfunctions rely on understanding the molecular mechanisms of chemobrain. Importantly, strong evidences correlating neuronal injury, inflammation and consequent immunological events, with the development of chemobrain have sparked greatly (Wang et al., 2015). However, the mechanisms by which neuro-inflammatory events crosstalk with immune-regulatory and neural homeostasis hallmarks in chemobrain are still unclear. Hence, understanding and targeting these pathways can act as a gold standard in treating chemobrain.

It is important to mention that numerous reports demonstrated that DOX does not cross the blood brain barrier (BBB) (Cardoso et al., 2008; Tangpong et al., 2006, 2007). However, DOX treatment still causes brain injury via alterations in the cytokine milieu (Keeney et al., 2018; Lyon et al., 2014). One of these causative cytokines is the tumor necrosis factor-alpha (TNF-α) (El-Agamy et al., 2019). Mechanistically, DOX undergoes redox cycling to produce superoxide free radical in the peripheral tissues. This leads to oxidative modification of a key plasma protein, apolipoprotein A1 (ApoA1). Oxidized ApoA1 in turn, leads to increased peripheral TNFα that crosses the BBB to induce brain oxidative stress which negatively affects brain mitochondria leading to apoptotic cell death, subsequently resulting in chemobrain (Butterfield, 2014). Furthermore, TNF-α is a well-established potent pro-inflammatory cytokine. It has a pleiotropic effect and is considered a master regulator of cellular cascades that controls cell viability, gene expression and synaptic integrity (Wajant et al., 2003). Targeting TNF-α have been elucidated to ameliorate neuro-inflammation in neurodegenerative diseases such as Alzheimer's disease, Parkinson's diseases, infection related dementia as well traumatic brain injury (Frankola et al., 2011). Moreover, the anticancer activity of infliximab in patients was previously proved in different types of tumors (Larkin et al., 2010; Li and Jian, 2018). It was also reported that infliximab may sensitize colon cancer cells to oxaliplatin treatment (Huang et al., 2018).

On the other hand, Type I interferons (IFNs) are cytokines with wide range of immunoregulatory properties affecting cell proliferation. One subtype is IFN-beta-1a (IFN-β-1a) which possess immune-modulatory activities and is considered among first-line treatment for treating multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) (Kasper and Reder, 2014; Sattler et al., 2006). Mechanistically, it may alter the balance of immunoregulatory and pro-inflammatory milieu by inhibiting T-cell inflammatory response, thus, inducing an anti-inflammatory status in MS patients (Mirandola et al., 2009; Severa et al., 2015). Interestingly, studies showed that IFN-β-1a directly controls neural progenitor cells apoptosis, which may serve a neuroprotective role in the central nervous system (CNS) (Hirsch et al., 2009). Additionally, IFN-β-1a was proved to regulate neuronal autophagy in Parkinson's diseases (Ejlerskov et al., 2015). Importantly, experimental studies (Damdinsuren et al., 2003) and clinical trials have established a number of indications for IFNs in different hematological and solid tumors (Jonasch and Haluska, 2001). It was also previously reported that the use of peg–IFN–β-1a significantly improved the antitumor activity of chemotherapy in breast and renal carcinomas (Boccia et al., 2017).

Interestingly, the crosstalk between type I IFN and TNFα was proposed earlier in several studies (Hu et al., 2008; Palucka et al., 2005; Sweiss et al., 2011), where several immune-based diseases can be viewed as a disequilibrium between both cytokines (Cantaert et al., 2010). Both cytokines have pleiotropic effect and with respect to their signaling crosstalk, it could be either induction (cross priming) or inhibition (cross regulation) of each other, depending on the type of stimulus. Such observed discrepancy is likely caused by different experimental conditions as well as different type of the disease (Cantaert et al., 2010; Yarilina et al., 2008). Hence, the molecular mechanisms of their cross talk and understanding their interplay in neurodegenerative diseases remain unclear demanding further extensive investigations. Besides, neither administration of IFN-β-1a or TNF-α inhibitor has been studied in DOX-induced chemobrain. In this regard, this study aimed to examine the potential neuroprotective effects of IFN-β-1a, as well as TNF-α inhibitor in DOX-induced chemobrain in rats. Besides, the current study targets investigating the possible underlying mechanisms in terms of neuromodulation, neuroinflammation as well as interference with neural homeostasis hallmarks.