Liver X Receptor Activation with an Intranasal Polymer Therapeutic Prevents Cognitive Decline without Altering Lipid Levels

Abstract

The progressive accumulation of amyloid-beta (Aβ) in specific areas of the brain is a common prelude to late-onset of Alzheimer’s disease (AD). Although activation of liver X receptors (LXR) with agonists decreases Aβ levels and ameliorates contextual memory deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits their clinical application. DMHCA ( N , N -dimethyl-3β-hydroxycholenamide) is an LXR partial agonist that, despite inducing the expression of apolipoprotein E (main responsible of Aβ drainage from the brain) without increasing cholesterol/triglyceride levels, shows nil activity in vivo because of a low solubility and inability to cross the blood brain barrier. Herein, we describe a polymer therapeutic for the delivery of DMHCA. The covalent incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate esters produces an amphiphilic copolymer that efficiently self-assembles into nanometric micelles that exert a biological effect in primary cultures of the central nervous system (CNS) and experimental animals using the intranasal route. After CNS biodistribution and effective doses of DMHCA micelles were determined in nontransgenic mice, a transgenic AD-like mouse model of cerebral amyloidosis was treated with the micelles for 21 days. The benefits of the treatment included prevention of memory deterioration and a significant reduction of hippocampal Aβ oligomers without affecting plasma lipid levels. These results represent a proof of principle for further clinical developments of DMHCA delivery systems.

Altered Cholesterol Homeostasis in Huntington’s Disease

“…Manipulating LXR activity offers new therapeutic strategies in HD but the clinical use of these compounds is limited to the peripheral hypercholesterolemia/hypertriglyceridemia undesirable side effects. To counteract this limitation, new compounds and tools need to be designed with better brain specificity and with limited lipogenic effects attributed to LXRα in peripheral tissues ( Stachel et al, 2016 ; Navas Guimaraes et al, 2021 ).…”

Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain

“…This would also function as a potential nanodrug therapy for AD treatment via IN route. [ 141 ] Table 3 summarizes various therapeutic agents based on their polymeric systems and IN delivery.…”

“…What is more, a nil side effect is found during the 21‐day treatment with the dose of 3 mg/kg body weight/day, which unveils the PEG‐[G1]‐DMHCA is safe and biocompatible, rendering it an ideal drug delivery system to remedy cognitive deficits. [ 141 ]…”

“…For instance, prolonged circulation times, desirable biostability, specific-site release, and high drug encapsulation rate are essential characteristics. In one investigation, a type of hybrid NPs, with PLGA as a core polymer Unknown stability and pharmacokinetics [141] encapsulated with a layer of PEG and cationic lipids, were used to create a direct route of nose-to-brain transport, which was used for Farnesylthiosalicyclic acid (FTA) treatment in a mouse model of GBM. [62] The hybrid NPs were formulated via emulsion sonification, combining PLGA and FTA, then presented in the surrounding PEG and cationic lipids.…”

“…Currently, there are few exciting translational application reports regarding PEG-modified NPs in biomedical fields, namely, GBM treatment, [125] neuroprotection in PD, [140] and AD therapy. [141] Liu et al synthesized self-assembled nanoscavengers capable of cleaning alpha-synuclein, which is linked to the PD pathogenesis. Such approach could provide a pre-clinical path as a non-invasive therapeutic strategy for PD treatment via IN delivery.…”