Tackling neurodegeneration with by-product-based-nanohydrogels for the nose-to-brain-delivery of natural bioactive compounds
Progetto Neurodegenerative diseases, such as Alzheimer's disease, affecting millions of
people worldwide, are multifactorial disorders characterised by the progressive
loss of neurons in the central nervous system (CNS). Although each
neurodegenerative disease exhibits specific pathological features, they also
share some common molecular mechanisms, such as neuroinflammation and
oxidative stress, and ageing is the primary risk factor for most of them. The
lack of effective treatments and the complex nature of these diseases has
developed a pressing need to identify multitarget-directed ligands to address
the complementary pathways involved in these disorders. In this scenario,
natural bioactive compounds (NBCs) constitute a unique source of privileged
molecules with a safety profile and a vast multi-target potential. Among them,
sulforaphane (SFN), an isothiocyanate derived from glucoraphanin present in
Brassicaceae, and isoliquiritigenin (ILQ), a flavonoid compound mainly found
in the root of Glycyrrhiza Uralensis, have shown a great neuroprotective
potential. Even though their in vivo application is limited due to SFN relative
instability, and ILQ low bioavailability. On these bases, the aim of this project
is to design an innovative biopolymer based on the conjugation between
silkworm sericin by-product and hyaluronic acid, characterised by high
biocompatibility and tailorable biodegradation rate. This innovative
biomaterial will be exploited for the formulation of nanohydrogels (NG)
loaded with SFN and ILQ to be administered by nasal route (nose-to-brain-
delivery to bypassing blood brain barrier). External biocompatible and
biodegradable cross-linkers will be considered to tailor both the rheological
properties and the release behavior of the nanohydrogel.
We expect that the novel nanohydrogel has the potential to promote the
controlled release of the NBCs, increasing the CNS targeting. The
neuroprotective activity of the designed nanohydrogels will be investigated
both in vitro and in vivo models of neurodegeneration. Microglial BV-2 and
neuron-like SH-SY5Y cell cultures will be used to investigate the anti-
inflammatory and antioxidant activity of the new nanohydrogels while their
anti-ageing activity will be studied in astrocytes. The most effective
nanohydrogel will be further studied in two mice models of
neurodegeneration: proteolipid protein (PLP) induced experimental
autoimmune encephalomyelitis (EAE) in SJL mice, and myelin oligodendrocyte
glycoprotein (MOG)-induced EAE in C57Bl6 mice