Chemobrain, also known as chemotherapy-induced cognitive impairment, is a well-described adverse effect that inflicts cancer patients receiving chemotherapy. Chemobrain manifests several neurological changes, such as memory deficits, attention problems, and executive working dysfunction [1]. Several factors may contribute to the development and the complication of chemobrain including genetic and psychological factors, as well as the administration of chemotherapeutic drugs [2]. The underlying mechanisms for the development of chemobrain remain not fully understood. Nevertheless, it is suggested that oxidative stress, inflammation, and neurogenesis may play a role in the development and progression of chemobrain [3]. Previous research on both humans and animals highlighted the importance of the hippocampus and prefrontal cortex in memory function. The hippocampus plays a pivotal role in memory formation and can generate new neurons, while the prefrontal cortex is essential for recognition memory [4,5]. Methotrexate (MTX) treatment can result in severe neurotoxicity, particularly in the hippocampus, leading to reduced neurogenesis and memory deficits [6]. MTX also induces oxidative stress by generating reactive oxygen species (ROS), contributing to cell cycle arrest and cell death in the central nervous system [7]. The brain tissues are susceptible to oxidative damage due to their high metabolic rate, elevated polyunsaturated fatty acid content, and limited antioxidant capacity [8]. Moreover, the hippocampal dysfunction may cause memory impairment in patients receiving chemotherapy [9].

Empagliflozin (EMPA) is an antidiabetic drug in type 2 diabetes, which inhibits the sodium-glucose cotransporter-2 (SGLT2) [10]. Thus, EMPA lowers blood glucose levels by enhancing glucose excretion in urine through inhibition of renal glucose reabsorption [11]. In addition, EMPA is indicated to decrease the cardiovascular death risks [12]. Recent studies described promising neuroprotective effects of EMPA, since it protects the brain via diminishing oxidative stress, decreasing inflammation, and improving the vascular function and blood supply to the brain [13]. Hence, EMPA is considered a promising drug for the prevention of chemobrain.

Polylactide co-glycolide (PLGA) is a widely used polymer for drug delivery purposes. PLGA nanoparticles are commonly applied in various administration routes. Moreover, PLGA nanoparticles are biodegradable and biocompatible, FDA-approved for drug administration, suitable for sustained release, and amenable to surface modification with functional groups or targeting moieties. There are well-described techniques for preparation of PLGA nanoparticles and loading with hydrophilic and hydrophobic drugs [14,15]. Many studies demonstrated successful intranasal drug delivery using PLGA nanoparticles to the brain [16,17].

The available treatment options for central nervous system (CNS) disorders are usually oral or parenteral routes, which suffer from limited accessibility of the drug to the brain due to the presence of the blood brain barrier [18]. Furthermore, first-pass metabolism, enzymatic degradation, plasma protein binding, and systemic clearance of drugs decrease their bioavailability to the brain [19]. The intranasal drug delivery route represents a convenient and non-invasive pathway to bypass the blood brain barrier and deliver the drug payload directly to the CNS through the nasal cavity. Several studies confirmed that the intranasal route overcomes the limitations for CNS drug delivery and enhance the drug delivery to the brain [20,21]. Hence, enhanced brain delivery of insulin, oxytocin, and nerve growth factors was reported through the intranasal route [19,22]. Drug molecules, after application into the nasal cavity, should reach the brain through two main pathways, namely the neuronal and systemic circulation pathways. The drug passes to the posterior part of the nasal cavity where it directly transports to the brain via the olfactory nerve, trigeminal nerve, lymphatic and vestibular routes, and the cerebrospinal fluid [19,23]. Furthermore, small lipophilic drug molecules can pass through nasal capillaries to the systemic circulation and reach the CNS through the blood brain barrier [24,25]. Thus, intranasal drug delivery is a safe, non-invasive, and very effective modality for drug delivery of neuroprotective agents directly into the CNS [26]. Hence, our work aimed to study EMPA-loaded PLGA nanoparticles applied through the intranasal route and investigate their potential neuroprotective effects as an innovative strategy to counteract chemobrain in methotrexate-treated rats.