A Brain-Targeted Approach to Ameliorate Memory Disorders in a Sporadic Alzheimer’s Disease Mouse Model via Intranasal Luteolin-Loaded Nanobilosomes

Abstract

Impaired memory and cognitive function are the main features of Alzheimer’s disease (AD). Unfortunately, currently available treatments cannot cure or delay AD progression. Moreover, the blood–brain barrier hampers effective delivery of treatment to the brain. Therefore, we aimed to evaluate the impact of intranasally delivered luteolin on AD using bile-salt-based nano-vesicles (bilosomes). Different bilosomes were prepared using 23-factorial design. The variables were defined by the concentration of surfactant, the molar ratio of cholesterol:phospholipid, and the concentration of bile salt. Results demonstrated optimized luteolin-loaded bilosomes with particle size (153.2 ± 0.98 nm), zeta potential (−42.8 ± 0.24 mV), entrapment efficiency% (70.4 ± 0.77%), and % drug released after 8 h (80.0 ± 1.10%). In vivo experiments were conducted on an AD mouse model via intracerebroventricular injection of 3 mg/kg streptozotocin. We conducted behavioral, biochemical marker, histological, and immune histochemistry assays after administering a luteolin suspension or luteolin bilosomes (50 mg/kg) intranasally for 21 consecutive days. Luteolin bilosomes improved short-term and long-term spatial memory. They also exhibited antioxidant properties and reduced levels of proinflammatory mediators. They also suppressed both amyloid β aggregation and hyperphosphorylated Tau protein levels in the hippocampus. In conclusion, luteolin bilosomes are an effective, safe, and non-invasive approach with superior cognitive function capabilities compared to luteolin suspension.

Novel Luteolin-Loaded Chitosan Decorated Nanoparticles for Brain-Targeting Delivery in a Sporadic Alzheimer’s Disease Mouse Model: Focus on Antioxidant, Anti-Inflammatory, and Amyloidogenic Pathways

“…Many challenges exist that hamper drug targeting to the brain through either non-invasive enteral or invasive parenteral routes of administration [ 15 ]. Therefore, exploiting the intranasal route offers many advantages over both oral and parenteral routes including non-invasiveness, no need for sterile preparation, self-patient administration, shorter onset of action, and higher brain exposure by circumventing the intestinal/hepatic first-pass metabolism and bypassing the BBB [ 4 , 15 , 16 , 17 ]. Consequently, the intranasal route represents a promising route for direct non-invasive brain delivery, especially for diseases that require chronic treatment, such as AD.…”

Therapeutic considerations of bioactive compounds in Alzheimer's disease and Parkinson's disease: Dissecting the molecular pathways

“…Largely present in thyme, broccoli, celery, pepper, the 3′,4′,5,7‐tetrahydroxy flavone luteolin is reported to possess immense therapeutic abilities (Nabavi et al, 2015). The effective dose of luteolin as suggested by the studies is found to range within 50–80 mg/kg intranasally and intraperitoneally (Ahmad et al, 2021; Elsheikh et al, 2022) in AD animals, while it ranges from 10 to 50 μM in cell models of PD (Guo et al, 2013; Reudhabibadh et al, 2021; Wu et al, 2017). Luteolin is reported to decrease oxidative stress, neuroinflammation, inhibit AChE activity, BACE1 activity, suppress Aβ aggregation and tau hyperphosphorylation and attenuate cognitive abnormalities in Drosophila and mice models of AD (Ahmad et al, 2021; Ali et al, 2019; Elsheikh et al, 2022).…”

“…The effective dose of luteolin as suggested by the studies is found to range within 50–80 mg/kg intranasally and intraperitoneally (Ahmad et al, 2021; Elsheikh et al, 2022) in AD animals, while it ranges from 10 to 50 μM in cell models of PD (Guo et al, 2013; Reudhabibadh et al, 2021; Wu et al, 2017). Luteolin is reported to decrease oxidative stress, neuroinflammation, inhibit AChE activity, BACE1 activity, suppress Aβ aggregation and tau hyperphosphorylation and attenuate cognitive abnormalities in Drosophila and mice models of AD (Ahmad et al, 2021; Ali et al, 2019; Elsheikh et al, 2022). In cellular models of PD, luteolin is reported to counter oxidative stress, neuroinflammation, suppress α‐synuclein aggregation and protect dopaminergic cells from degeneration (Chen et al, 2008; Guo et al, 2013; Reudhabibadh et al, 2021; Wu et al, 2017).…”

“…However, luteolin possesses certain pharmacological limitations including rapid metabolism and poor bioavailability (Sarawek et al, 2008; Wang, Zeng, et al, 2021). Also, though luteolin is detected in the brain which indicates it can cross the BBB, this molecule is suggested to bear poor to moderate BBB permeability (Daily et al, 2021; Elsheikh et al, 2022). The beneficiary potential of kaempferol , a flavonoid abundantly found in a variety of natural sources including kale, berries, citrus fruits, green tea, beans and so on, is reported in various ailments including neurodegenerative diseases like AD and PD (Siddique, 2021).…”

Nano-scale drug delivery systems for luteolin: advancements and applications

“…Furthermore, intranasal drug delivery formulations, including chitosomes, nanoemulsions, and bilosomes, have been developed to facilitate brain-targeted drug delivery of Lu. 90,106,109 This approach increases bioavailability by facilitating the transport of drugs through the blood-brain barrier, offering an effective, non-invasive, and safe method of drug administration. This review also introduces the advancements and applications of Lu-loaded nano-scale drug delivery systems in the treatment of various diseases, as illustrated in Fig.…”