In recent decades, the emergence of neurological disorders has become increasingly prevalent among chemotherapy patients, posing serious complications. According to previous reports, 15–80 % of patients experience cognitive dysfunction and depression as a consequence of chemotherapy exposure [1], [2]. The observed neurotoxic manifestations encompass seizures, stroke, encephalopathy, locomotion impairment, cranial neuropathy and peripheral neuropathy [3]. Chemotherapy-induced cognitive impairment [4] and associated co-morbidities occur when the anticancer agents cause disruption and successfully traverses the blood brain barrier (BBB). The precise mechanism underlying neurotoxicity caused by anticancer agents remains elusive. However, existing literature suggests that various mechanisms, such as direct neuronal damage, modulation of neurotransmitter levels, induction of oxidative stress, impairment of immune function, and hypoxia, likely contribute to the manifestation of this toxic effect [5].

Cyclophosphamide (CYP), an immunosuppressive and antineoplastic agent, suppresses malignant cell growth and decreases cancer survival. The metabolites phosphoramide mustard and acrolein cause neurotoxicity, hepatotoxicity, immunotoxicity, and nephrotoxicity [6], [7]. Recent research indicates that the neurotoxic effects of CYP via inflammatory cytokines are becoming more apparent [8], [9]. Studies have observed that acrolein initiates lipid peroxidation, subsequently leads to the release of reactive oxygen species (ROS), causing cell injury [10]. Specifically, the brain tissues are highly susceptible to oxidative damage due to their limited antioxidant capacity [11]. Neurons and other brain cells lack the capability to synthesize reduced glutathione (GSH), thus relying on neighboring astrocytes to provide the necessary GSH precursors [12]. Furthermore, numerous studies have suggested that persistent inflammatory responses, coupled with the significant release of pro-inflammatory cytokines such as TNF-α and interleukins (IL), play a pivotal role in neurodegeneration linked with chemotherapy. In this context, various inflammatory signaling pathways, encompassing NF-κB, TLR, and NLRP3, are considered crucial components in the development of chemotherapy-induced neuronal inflammation [13]. Moreover, recent findings have confirmed that chemotherapy-related cognitive decline is strongly linked to impaired cholinergic function and the depletion of neuronal stores of acetylcholine, which is recognized as the primary neurotransmitter essential for maintaining normal cognition, learning, and memory [14], [15]. This phenomenon can be attributed to the increased production and activation of the acetylcholinesterase enzyme, which breaks down acetylcholine, leading to its degradation and ultimately disrupting cholinergic neurotransmission across synapses [16].

After cellular death, all organs endure sterile inflammation. The nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, which causes intracellular inflammation, can be triggered by various signals, such as cellular damage or pathogen-associated molecules. Furthermore, NLRP3 inflammasome has been implicated in the development of chronic degenerative diseases [17], [18]. The assembly and activation of the NLRP3 inflammasome involve the enzymatic activity of cleaved caspase-1 (CASP-1), which converts pro-inflammatory cytokines, such as IL-1β and IL-18, into their mature forms. Moreover, the mature cytokines released as a result of NLRP3 inflammasome activation boost the innate immune response and induce inflammation [19]. The production of IL-1β and IL-18 by the innate immune system has been found to be associated with experimental brain damage [20]. They stimulate macrophage inflammatory protein 2 (MIP2) chemokine production, thereby enhancing the proliferation of neutrophils within the brain during acute and chronic injury [21]. Furthermore, during brain injury, the disruption of the BBB allows the infiltration of inflammatory signals into the peripheral circulation via the bloodstream, thus triggering a systemic immunological response. These inflammatory signals have been shown to promote tissue repair and enhance the regeneration of nerves and blood vessels [22]. Therefore, NLRP3 inflammasome may represent a novel therapeutic target for a range of inflammatory conditions, such as autoimmune diseases, neurodegenerative disorders, and metabolic syndromes [23], [24].

Despite ongoing efforts to advance pharmaceutical interventions, the complex nature of neurological disorders has unfortunately resulted in a lack of promising therapeutic options. Some studies have suggested that the use of antihypertensive medications for managing hypertension could be a viable approach to prevent cerebral disorders [25], [26], [27]. However, the experimental findings continue to spark debates within the scientific community, highlighting the need for further investigations to establish a consensus regarding the efficacy of antihypertensive medications [28], [29], [30]. Irbesartan (IRB), an angiotensin II type 1 receptor (AT1R) antagonist, has the potential to inhibit apoptotic cell death, inflammatory chemokines and ROS production [31], [32]. Although IRB has been utilized in the management of various neurological conditions due to its ability to traverse the BBB [31], the precise impact of IRB on neurotoxicity has not been assessed. Thus, this study aims to assess, for the first time, the immunomodulatory effects of IRB on CYP-induced neurotoxicity by evaluating the oxidative stress and NLRP3 inflammasome pathways.