Alzheimer’s disease (AD) stands out as one of the prevailing neurodegenerative conditions among the elderly, and unfortunately, there exists no effective medication for its treatment. In our pursuit to address this critical gap, we employed a methodology involving the intracerebroventricular (icv) injection of streptozotocin (STZ) and intrahippocampal (ih) injection of amyloid-beta (Aβ1-42) administered consecutively over a span of 4 days. This approach was employed to establish a robust animal model replicating sporadic Alzheimer’s disease (sAD). Our primary objective was to assess the therapeutic efficacy of an equilibrative nucleoside transporter (ENT)1 inhibitor in the treatment of sAD.
Following the oral administration of the ENT1 inhibitor, we meticulously evaluated various parameters associated with AD pathology. These included the expression levels of pathological hallmarks such as amyloid-beta plaques and phosphorylated tau proteins, indicative factors of apoptosis, markers of broken DNA double-strand, nitrite levels as indicators of oxidative stress, cholinergic cell count, and performance in cognitive tasks such as the Morris water maze (MWM) and novel object recognition (NOR). Additionally, we monitored the 24-hour sleep-wake activity by analyzing electroencephalogram (EEG) and electromyogram (EMG).
Our results revealed promising outcomes, showcasing that the ENT1 inhibitor successfully impeded the escalation of nitric oxide, caspase 3, and phosphorylated γ-H2AX. Furthermore, it facilitated the augmentation of activities related to nuclear DNA-dependent serine/threonine protein kinase (DNA-PKcs) through the non-homologous end joining (NHEJ) pathway, effectively repairing DNA double-strand breaks. Notably, the ENT1 inhibitor demonstrated a mitigating effect on cholinergic neuronal loss in sAD mice and led to improvements in cognitive deficits observed in the MWM and NOR tasks.
Moreover, in the realm of sleep patterns, sAD mice exhibited altered sleep architecture, characterized by increased non-rapid eye movement (NREM) sleep during the dark period and decreased NREM and rapid eye movement (REM) sleep during the light period. Remarkably, the administration of the ENT1 inhibitor resulted in the elevation of extracellular adenosine, proving beneficial in restoring homeostatic sleep.
In conclusion, our findings suggest that the ENT1 inhibitor holds promise as a potential therapeutic intervention for the treatment of sAD and its associated disruptions in sleep patterns. This research signifies a step forward in addressing the challenges posed by Alzheimer's disease and offers a novel avenue for future investigations into neurodegenerative disorders.