Thesis title: Advanced strategies for delivering neuroprotective substances to the brain in neurodegenerative disease
Neurodegenerative diseases (ND) represent a significant health issue, leading to increased disability, medical treatment, and prolonged care, especially with the aging population. ND are often associated with atrophy in the central or peripheral nervous system, declining neurological function, and neuronal death. Current therapeutic strategies for ND primarily alleviate symptoms without offering disease-modifying effects. In this light, current interest in natural-derived medications have shown promise for new ND treatments exhibiting various neurofunctional benefits, including anti-inflammatory and neuroprotective effects due to their pleiotropic action. However, natural compounds face significant limitations in reduced bioavailability due to their sensitivity to chemical and physical degradation, rapid metabolism, and inability to cross the blood-brain barrier (BBB), leading to poor brain accumulation. Effective treatment of ND requires BBB penetration where advanced nanotechnology and specific administration routes, such as Nose to Brain (NtB) delivery via colloidal systems, are crucial.
This thesis focuses on Ellagic Acid (EA), a natural compound mostly known for improving memory and cognitive deficits, and its activities in an ex vivo Alzheimer’s disease model.
In this work, it was investigated EA's impact on hippocampal synaptic plasticity and neuroprotection against Amyloid beta (Aβ1-42)-induced impairments using electrophysiological recordings, including extracellular field and whole-cell patch clamp recordings. EA demonstrated the ability to modulate synaptic plasticity at high concentrations and rescue Long-Term Potentiation (LTP) impairment and basal neurotransmission alteration following Aβ1-42 application, suggesting its therapeutic potential in the treatment of cognitive disorders.
However, its use in neuropharmacology fields is embedded by its low water solubility and extensive first-pass metabolism with, consequently poor bioavailability. To address this, EA was encapsulated in non-ionic surfactant vesicles (NSVs), designed, and characterized for the supposed Nose to Brain (NtB) delivery. The final EA-NSVs formulation showed neuroprotective effects at lower doses compared to free EA, as evidenced by the rescue of Aβ1-42-induced LTP impairment. Additionally, in this work of thesis, another NtB delivery strategy have been designed based on the development of non-ionic surfactant based nanobubbles (VBNs), supposed to be delivered intranasally in mixture with EA-NSVs. Indeed, nanobubbles, combined with low-intensity focused ultrasound (US), offer a non-invasive method to transiently permeabilize the BBB. Specifically, in this work an in vitro US characterization protocol for VNBs was developed, suggesting stable and controlled probe release, supporting their potential in vivo application combined with EA-NSVs for ND treatment, specifically in cognitive disorders, such as AD.