In vitro and in vivo evaluation of multi-target-directed Rivastigmine/Memantine/Gingko biloba-loaded nanofibers against Alzheimer's disease

Abstract

The highly complex pathophysiology of Alzheimer\"s disease (AD) and the low bioavailability of the currently used drugs make it necessary to offer versatile treatment options. In this study, polyvinyl alcohol (PVA)/polyvinylpyrrolidone (PVP) nanofibers (NFs) were loaded with rivastigmine (RIV), memantine (MM), and Gingko biloba (GB) extract, and their anti-Alzheimer\"s effects were investigated in vitro by cell culture and in vivo by animal experiments. The characterization studies, including FTIR, XRD, and DSC analysis, showed that the fibers exhibited a good compatibility. The rapid disintegration (in 5.2 s) and complete dissolution (in 120 s) of RIV/MM/GB-loaded NF indicated their suitability for sublingual application. Cell viability analysis revealed that RIV/MM/GB-loaded NFs can be considered as safe and promising candidates. RIV/MM/GB-loaded NFs tremendously improved the learning and memory impairment seen in the AD model created by the injection of intracerebroventricular-streptozotocin into rats. Moreover, RIV/MM/GB-loaded NF stimulated stem cells to improve neuronal differentiation properties and significantly decreased the level of β-amyloid, tau, APP, TNF-α, AChE, and GSK-3β in the brain. The histopathological and immunostaining assays demonstrated that RIV/MM/GB-loaded NF reduced β-amyloid formation and tau hyperphosphorylation in the hippocampus and cerebral cortex. Thus, a novel and promising treatment strategy could be developed that has several advantages, such as ease of sublingual administration, reduced frequency of administration associated with lower drug amounts, and finally reduced toxicity and cost.