Rational Design of a Theranostic Agent Triggered by Endogenous Nitric Oxide in a Cellular Model of Alzheimer’s Disease

What does this mean for all the benefits of getting nitric oxide?

• nitric oxide (107 posts to March 2011)

 

Ask your doctor for a specific analysis. I can't figure out what upregulated is.

Pathogenesis: the manner of development of a disease.

Rational Design of a Theranostic Agent Triggered by Endogenous Nitric Oxide in a Cellular Model of Alzheimer’s Disease

• Kang Lu
, 
• Yu Wang
, 
• Hao Zhang
, 
• Cuiqing Tian
, 
• Wenxiang Wang
, 
• Tian Yang
, 
• Baiwen Qi
, and 
• Song Wu*

Cite this: J. Med. Chem. 2022, XXXX, XXX, XXX-XXX

Publication Date:June 21, 2022

https://doi.org/10.1021/acs.jmedchem.2c00399

Abstract

Oxidative damage caused by upregulated nitric oxide (NO) plays an important role in the pathogenesis of Alzheimer’s disease (AD). Currently, stimulus-triggered theranostic agents have received much attention due to benefits on disease imaging and targeted therapeutic effects. However, the development of a theranostic agent triggered by NO for AD remains unexplored. Herein, through the mechanism analysis of the reaction between a fluorophore of 9,14-diphenyl-9,14-dihydrodibenzo[a,c]phenazine (DPAC) and NO, which we occasionally found and thereafter structure optimization of DPAC, a theranostic agent DPAC-(peg)₄-memantine was fabricated. In an AD cellular model, DPAC-(peg)₄-memantine exhibits NO sensing ability for AD imaging. Meanwhile, DPAC-(peg)₄-memantine shows improved therapeutic by targeted drug release triggered by NO and sustained therapeutic effects owing to the synergetic antioxidative abilities via the anti-AD drug and NO scavenging. This work provides an unprecedented avenue for the studies on not only AD but also other diseases with NO upregulation.

Supporting Information

---

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00399.

• Molecular formula strings (CSV)

• The proposed reaction mechanism of DPAC with NO; NMR, HRMS, and HPLC analysis of the reaction mechanism; detection limit of DPAC-(peg)₄-memantine with NO; the parallel artificial membrane permeability assay (PAMPA) of DPAC-(peg)₄-memantine; time-dependent effects of DPAC-(peg)₄-memantine and the related drugs on HT22 cells under the coculture system; the LIVE/DEAD staining of HT22 cells under the coculture system with 9,10-PAQ and p-benzoquinone; Glu release on HT22 cells under the coculture system with HO-(peg)₄-memantine and memantine¹; and H,¹³C NMR, and HRMS spectra of the products (PDF)