Endogenous Conjugation of Biomimetic Dinitrosyl Iron Complex with Protein Vehicles for Oral Delivery of Nitric Oxide to Brain and Activation of Hippocampal Neurogenesis

Abstract

Nitric oxide (NO), a pro-neurogenic and antineuroinflammatory gasotransmitter, features the potential to develop a translational medicine against neuropathological conditions. Despite the extensive efforts made on the controlled delivery of therapeutic NO, however, an orally active NO prodrug for a treatment of chronic neuropathy was not reported yet. Inspired by the natural dinitrosyl iron unit (DNIU) [Fe(NO)₂], in this study, a reversible and dynamic interaction between the biomimetic [(NO)₂Fe(μ-SCH₂CH₂OH)₂Fe(NO)₂] (<b>DNIC-1</b>) and serum albumin (or gastrointestinal mucin) was explored to discover endogenous proteins as a vehicle for an oral delivery of NO to the brain after an oral administration of <b>DNIC-1</b>. On the basis of the in vitro and in vivo study, a rapid binding of <b>DNIC-1</b> toward gastrointestinal mucin yielding the mucin-bound dinitrosyl iron complex (DNIC) discovers the mucoadhesive nature of <b>DNIC-1</b>. A reversible interconversion between mucin-bound DNIC and <b>DNIC-1</b> facilitates the mucus-penetrating migration of <b>DNIC-1</b> shielded in the gastrointestinal tract of the stomach and small intestine. Moreover, the NO-release reactivity of <b>DNIC-1</b> induces the transient opening of the cellular tight junction and enhances its paracellular permeability across the intestinal epithelial barrier. During circulation in the bloodstream, a stoichiometric binding of <b>DNIC-1</b> to the serum albumin, as another endogenous protein vehicle, stabilizes the DNIU [Fe(NO)₂] for a subsequent transfer into the brain. With aging mice under a Western diet as a disease model for metabolic syndrome and cognitive impairment, an oral administration of <b>DNIC-1</b> in a daily manner for 16 weeks activates the hippocampal neurogenesis and ameliorates the impaired cognitive ability. Taken together, these findings disclose the synergy between biomimetic <b>DNIC-1</b> and endogenous protein vehicles for an oral delivery of therapeutic NO to the brain against chronic neuropathy.