The current pharmacological treatment of Huntington's disease (HD) is palliative, and therapies to restore functions in patients are needed. One of the pathways affected in HD involves brain cholesterol (Chol) synthesis, which is essential for optimal synaptic transmission. Recently, it was reported that in a HD mouse model, the delivery of exogenous Chol to the brain with brain-permeable nanoparticles protected animals from cognitive decline and rescued synaptic communication, indicating Chol as a therapeutic candidate. We examined whether nose-to-brain delivery, already used in human therapy, could be an alternative, noninvasive strategy to deliver Chol to the adult brain and, in the future, replenish Chol in the HD brain. We gave wild-type (WT) mice a single intranasal (IN) dose of liposomes loaded with deuterium-labeled cholesterol (Chol-D6, to distinguish and quantify the exogenous cholesterol from the native one) (200 μg Chol-D6/dose). After different intervals, Chol-D6 levels, determined by LC-MS in plasma, striatum, cortex, and cerebellum, reached a steady-state concentration of 0.400 ng/mg between 24 and 72 h. A subsequent acute study confirmed the kinetic profiles of Chol-D6 in all tissues, indicating correspondence between the dose (two doses of 200 μg Chol-D6/dose) and the calculated brain area concentration (0.660 ng/mg). Finally, in WT mice given repeated IN doses, the average Chol-D6 level after 24 h was about 1.5 ng/mg in all brain areas. Our data indicate the effectiveness of IN Chol-loaded liposomes to deliver Chol in different brain regions, opening the way to future investigations in HD mice.
|Titolo:||Efficacy of Cholesterol Nose-to-Brain Delivery for Brain Targeting in Huntington's Disease|
|Parole Chiave:||Huntington’s disease; LC-MS analysis; brain cholesterol; intranasal administration; liposomes; nose-to-brain delivery|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||5-feb-2020|
|Data ahead of print / Data di stampa:||7-gen-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/acschemneuro.9b00581|
|Appare nelle tipologie:||01 - Articolo su periodico|