Evaluation of the Effect of Amantadine in the Prevention of Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients

Cancer persists as a predominant contributor to global morbidity and mortality (DeSantis et al., 2016) . Despite the established cytotoxic efficacy of chemotherapeutic agents in impeding tumor progression through the eradication of highly proliferative malignant cells, their clinical utility is frequently constrained by deleterious systemic toxicities. Among these, chemotherapy-induced peripheral neuropathy (CIPN) constitutes a severe, dose-limiting clinical toxicity associated with specific chemotherapeutic regimens (Zhang et al., 2017) . For a substantial proportion of patients, CIPN manifests as profoundly debilitating symptoms that compromise functional independence and activities of daily living (ADL), alongside a significant deterioration in health-related quality of life (QoL). Such clinical deterioration often mandates therapeutic dose attenuation and/or treatment delays, leading to suboptimal oncological outcomes and the prolongation of therapeutic cycles.(Smith et al., 2013a) This neurotoxicity is strongly associated with specific classes of cytotoxic agents, including taxanes, platinum-based compounds, and vinca alkaloids, as well as immunomodulatory agents such as thalidomide and lenalidomide, and the proteasome inhibitor bortezomib (Kottschade et al., 2011) . Although prospective identification of patients predisposed to CIPN presents a significant clinical challenge, established risk factors encompass antecedent exposure to neurotoxic agents, diabetes mellitus, folate or vitamin B12 deficiencies, African ethnicity, and advanced age (Brewer et al., 2016) . Paclitaxel represents a first-line chemotherapeutic modality for solid tumors. Its principal antineoplastic mechanism involves the disruption of mitotic spindle assembly and microtubule dynamics, ultimately triggering apoptotic cell death. Nevertheless, the major dose-limiting toxicity associated with its clinical use is dose-dependent sensory peripheral neuropathy )(Duggett et al., 2016; Scripture et al., 2006) . The incidence of paclitaxel-induced peripheral neuropathy (PIPN) can reach up to 97% among treated patients, with a chronic course observed in more than 60% of cases (Tanabe et al., 2013) . The initial clinical manifestations of PIPN encompass paresthesia (numbness and tingling) and/or allodynia, defined as painful sensations elicited by normally non-noxious stimuli-which may develop in the patient's fingers and toes within 24 to 72 hours post-injection. These sensory symptoms may subsequently progress to involve the lower legs and wrists in a characteristic "glove and stocking" distribution. Typically, symptoms initiate distally and advance proximally in tandem with clinical deterioration (Argyriou et al., 2008; Smith et al., 2013b) . The pathogenesis of paclitaxel-induced peripheral neuropathy is multifactorial, primarily driven by the generation of reactive oxygen species (ROS)-including superoxide, hydroxyl radicals, nitric oxide, and hydrogen peroxide-within neuronal mitochondria. This oxidative stress is accompanied by the elaboration of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), largely secondary to the activation of microglia and astrocytes, alongside other interconnected mechanisms (Carvalho et al., 2017; Sisignano et al., 2014) . Glutamate serves as the principal excitatory neurotransmitter, orchestrating essential physiological processes such as learning and memory. Elevated concentrations of glutamate are implicated in excitotoxic cascades that culminate in neuronal death (Willard \& Koochekpour, 2013) . In rodent models treated with paclitaxel, the baseline frequency of excitatory postsynaptic currents was significantly elevated; notably, N-methyl-D-aspartate (NMDA) receptor antagonists completely normalized this aberrant frequency (Xie et al., 2016) . Furthermore, NMDA receptor signaling and glutamatergic pathways have been strongly implicated in the genesis of neuronal hyperexcitability. Consequently, the authors posited a pivotal therapeutic role for NMDA receptor antagonism in mitigating taxane-induced neuropathy (Drummond et al., 2024) . Correspondingly, Mihara et al. Delineated the involvement of NMDA receptors in the pathophysiology of oxaliplatin-induced mechanical allodynia in rodent models (Mihara et al., 2011) . The NMDA receptor is an ionotropic channel integral to mediating glutamatergic neurotransmission. Excessive activity of this receptor is pathogenically linked to spasticity alongside acute pain manifestations, which, if left untreated or if the ongoing insult persists, invariably progress to chronic neuropathic pain. Concurrently, NMDA receptor activation facilitates the release of substance P within the dorsal horn, thereby propagating central sensitization through synaptic remodeling. This process is further potentiated by augmented glutamate release via presynaptic NMDA receptors (Pușcașu et al., 2024) . Considering the complex and multifactorial nature of PIPN, an ideal therapeutic intervention would need to address both its central and peripheral components. The central mechanism is characterized by NMDA receptor-driven hyperexcitability, which preclinical studies have demonstrated can be attenuated by NMDA antagonists (Xie et al., 2016). In parallel, the peripheral mechanism is primarily mediated by oxidative stress and neuroinflammation, evidenced by the accumulation of reactive oxygen species (ROS) and pro-inflammatory cytokines, including TNF-α and IL-6 (Sisignano et al., 2014; Carvalho et al., 2017). Therefore, a drug that combines NMDA receptor antagonism with antioxidant and anti-inflammatory actions may provide a more comprehensive neuroprotective strategy. Amantadine, a non-competitive NMDA receptor antagonist that also possesses antioxidant and anti-inflammatory properties, emerges as a rational candidate for such a dual-action approach. Nevertheless, its role in preventing PIPN has not yet been investigated. To date, no approved therapeutic interventions exist for the prevention of PIPN. Although numerous agents have been investigated for the management of CIPN, duloxetine remains the only therapeutic option with established clinical efficacy. Consequently, further research is imperative to develop both preventive and ameliorative strategies for PIPN (Jordan et al., 2020; Loprinzi et al., 2020) . Amantadine is a non-competitive NMDA receptor antagonist that mitigates neuronal excitotoxicity by attenuating the prolonged influx of calcium ions, while preserving physiological NMDA receptor function (Blanpied et al., 2005) . Beyond its central action, amantadine has demonstrated significant antioxidant and anti-inflammatory properties in preclinical models. Specifically, it elevated glutathione (GSH) levels and reduced lipid peroxidation (LP), alongside downregulating pro-inflammatory cytokines such as TNF-α and IL-6 in a vincristine-induced peripheral neuropathy model (Drummond et al., 2024) . This dual mechanism-central NMDA receptor antagonism coupled with peripheral antioxidant and anti-inflammatory neuroprotection-positions amantadine as a rationally targeted and promising candidate for the prevention of PIPN, a condition in which both pathways are critically implicated. The therapeutic potential of amantadine in neuropathic pain has been supported by both clinical and preclinical investigations. Clinically, a double-blind, randomized, placebo-controlled trial demonstrated that intravenous amantadine infusion produced an average pain reduction of 85% in cancer patients with surgical neuropathic pain, compared with 45% following placebo administration, establishing it as a safe and effective acute treatment (Pud et al., 1998) . Similarly, a pilot study in patients with painful diabetic peripheral neuropathy showed that intravenous amantadine provided sustained pain relief for at least one week post-infusion (Amin \& Sturrock, 2003) . Preclinically, amantadine has demonstrated antinociceptive, anti-inflammatory, and antioxidant effects in a vincristine-induced peripheral neuropathy model in rats (Drummond et al., 2024) . Mechanistically, amantadine treatment significantly decreased lipid peroxidation (LP) and increased glutathione (GSH) levels in injured neural tissue, effects mediated through NMDA receptor antagonism (Mata-Bermudez et al., 2021). These dual findings-clinical analgesic efficacy and preclinical neuroprotective mechanisms-provide a strong rationale for investigating amantadine as a preventive strategy for PIPN.