Therapeutic Potential of Stearylamine-Conjugated Phenylboronic Acid-Modified Nanocarriers of 4-Allyl Pyrocatechol in Modulating Sialylation and Neuroinflammation in Scopolamine-Induced Cognitive Impairment in the Rat Model.

Alzheimer's disease is a progressive neurodegenerative condition and is regarded as the most prevalent type of dementia among older adults. It is characterized by the accumulation of beta-amyloid, tau protein hyperphosphorylation, cholinergic dysfunction, oxidative stress, neuroinflammation, and neuronal loss, all of which contribute to the gradual decline in cognitive function. Recent research has highlighted the role of sialylation in the pathogenesis of Alzheimer's disease. Sialylation plays a critical role in the pathophysiology of Alzheimer's disease, influencing amyloid plaque formation, neuroinflammation, and synaptic function. CD33 plays a significant role in regulating immune responses, particularly in the central nervous system, and has been implicated in the progression of Alzheimer's disease. In this study, we explore the neuroprotective effect of stearylamine-conjugated phenyl boronic acid-modified 4-allyl pyrocatechol (PAPS) nanoparticles in modulating sialylation and neuroinflammation against scopolamine-induced Alzheimer's disease in rats. 4-Allyl pyrocatechol is known to possess antioxidant and anti-inflammatory activities. On the other hand, stearylamine-conjugated phenyl boronic acid (PBSA) not only is a potential vehicle for delivering drugs or therapeutic agents to the brain but also has a propensity to inhibit the interaction of sialic acid-conjugated ligands with CD33 receptors, which facilitates clearance of amyloid beta through microglia-mediated phagocytosis. A total of 36 animals were divided into 6 groups (n = 6) as control group, disease group, standard group, PBSA carrier group, 4-allyl pyrocatechol group, and PAPS group, which were treated with 5% carboxy methyl cellulose (p.o.), scopolamine 3 mg/kg (i.p.), donepezil 3 mg/kg (i.p.), stearylamine-conjugated phenyl boronic acid 2 mL/kg (p.o.), 4-allyl pyrocatechol 10 mg/kg (p.o.), and PAPS 10 mg/kg (p.o.) respectively. The study was designed for 16 days. From day 8, all the groups except the control group were administered scopolamine 3 mg/kg (i.p.) 45 min before they were given their respective treatments. Behavioral tests (open field test, novel object recognition test, Y-maze, and Morris' water maze) were conducted from day 8 to day 15. On day 16, animals were euthanized by cervical dislocation, brains were isolated, and the hippocampus and prefrontal cortex were separated and homogenized, followed by centrifugation at 4 °C, 10,000 rpm for 15 min. The biochemical estimations like acetylcholinesterase activity were used; oxidative and antioxidant parameters like nitric oxide, malondialdehyde, and reduced glutathione were determined; enzyme-linked immunosorbent assays for amyloid beta, inflammatory cytokines, brain-derived neurotrophic factor, and CD33 were performed. The results from behavioral and biochemical tests suggested that the PAPS formulation had a more significant impact on slowing the progression of scopolamine-induced cognitive impairment compared to the stearylamine-conjugated phenyl boronic acid carrier and 4-allyl pyrocatechol alone treatments. The histopathological studies revealed a decline in neural degeneration and showed improved neuronal morphology in the PAPS-treated group compared with the disease group. From the data obtained, the PAPS nanoparticle formulation would be an effective strategy for reducing the progression of cognitive impairment.