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

Cheng Ru Wu, Yi Da Huang, Yong Huei Hong, Ya Hsin Liu, Manmath Narwane, Yu Hsiang Chang, Trinh Kieu Dinh, Hsin Tzu Hsieh, Yi Jen Hseuh, Ping Ching Wu, Chih Wen Pao, Ting Shan Chan, I. Jui Hsu, Yunching Chen, Hung Chi Chen, Ting Yu Chin, Tsai Te Lu

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

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] (DNIC-1) 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 DNIC-1. On the basis of the in vitro and in vivo study, a rapid binding of DNIC-1 toward gastrointestinal mucin yielding the mucin-bound dinitrosyl iron complex (DNIC) discovers the mucoadhesive nature of DNIC-1. A reversible interconversion between mucin-bound DNIC and DNIC-1 facilitates the mucus-penetrating migration of DNIC-1 shielded in the gastrointestinal tract of the stomach and small intestine. Moreover, the NO-release reactivity of DNIC-1 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 DNIC-1 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 DNIC-1 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 DNIC-1 and endogenous protein vehicles for an oral delivery of therapeutic NO to the brain against chronic neuropathy.

Original languageEnglish
Pages (from-to)998-1013
Number of pages16
JournalJACS Au
Volume1
Issue number7
DOIs
Publication statusPublished - 2021 Jul 26

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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