A BBB-Permeable Antioxidant Targeting Alzheimer’s Amyloidogenesis

Background: The clinical benefits of current antioxidant therapy for Alzheimer's disease (AD) are limited due to their poor disease target specificity. Our long-term objective is thus to design target-specific antioxidants and better understand their pharmacological mechanisms for AD and other human diseases, based on an emerging "pharmacophore conjugation" concept for drug development. The specific hypothesis for this studyl is that amyloid-targeting antioxidants assume targeted interdictions against cerebral Aβ amyloid pathology.Methods: We have rationally designed, synthesized, and characterized a novel bifunctional antioxidant- XH2A with chemically conjugated amyloid binding (benzothiazole) and antioxidant (lipoate) moieties. We have performed in sillico, cell culture and animal studies to characterize its partial pharmacological properties.Results: In sillico, cellular, and animal studies on XH2A indicated that: (i) XH2A molecule has only one NH group (<5 hydrogen-bond donors), two N and one O atoms (<10 hydrogen bond acceptors), MW=414 (<500). It agrees well with the general Lipinski's Rule of Five; (ii) XH2A interacts with Aβ1-40 peptide computationally and has an affinity binding constant of KD=4.43 μM toward monomeric Aβ1-40 peptide as determined by the SPR (surface plasmon resonance) technique; (iii) XH2A has no neurotoxicity at low micromolar concentrations, and it interdicted amyloid precursor protein (APP) translation (via its 5'UTR, IC50=50 nM) in human SH-SY5Y cells and attenuated cerebral Aβ amyloid pathology in PS1/APP doubly transgenic mice without inducing apparent animal toxicity and behavior disturbances; (iv) BBB penetration studies indicated that XH2A brain concentration can reach 16 nM (via oral route, a single gavage dose of 25 mg/kg) in mouse brain in just 2 hours. This is approximately 32% of its IC50=50 nM, and its brain to plasma concentration ratio is around 1:2.Conclusions: XH2A interdicts Alzheimer's Aβ amyloidosis both in vitro and in vivo. Thus, XH2A could be a novel brain-permeable antioxidant targeting Alzheimer's amyloidosis.