An Injectable Microparticle Formulation Provides Long-Term Inhibition of Hypothalamic ERK1/2 Activity and Sympathetic Excitation in Rats with Heart Failure

Youssef W. Naguib, Yang Yu, Shun Guang Wei, Angie Morris, Brittany E. Givens, Aml I. Mekkawy, Robert M. Weiss, Robert B. Felder, Aliasger K. Salem

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Sympathetic excitation contributes to clinical deterioration in systolic heart failure (HF). Significant inhibition of hypothalamic paraventricular nucleus (PVN) ERK1/2 signaling and a subsequent reduction of plasma norepinephrine (NE) levels in HF rats were achieved 2 weeks after a single subcutaneous injection of PD98059-loaded polymeric microparticles, without apparent adverse events, while blank microparticles had no effect. Similar reductions in plasma NE, a general indicator of sympathetic excitation, were previously achieved in HF rats by intracerebroventricular infusion of PD98059 or genetic knockdown of PVN ERK1/2 expression. This study presents a clinically feasible therapeutic approach to the central abnormalities contributing to HF progression.

Original languageEnglish
Pages (from-to)3643-3648
Number of pages6
JournalMolecular Pharmaceutics
Volume17
Issue number9
DOIs
StatePublished - Sep 8 2020

Bibliographical note

Funding Information:
This work was supported by National Institute of Health grants R01-HL-096671 and R01-HL-136149 to R.B.F. and S10-OD-019941 to R.M.W., by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, and by the Lyle and Sharon Bighley Chair of Pharmaceutical Sciences (A.K.S.). B.E.G. was supported by the National GEM Consortium, the Alfred P. Sloan Minority Ph.D. Scholarship, and the University of Iowa Graduate College Dean’s Fellowship.

Publisher Copyright:
Copyright © 2020 American Chemical Society.

Keywords

  • MEK1/2 inhibitor
  • PD98059
  • heart failure
  • hypothalamic paraventricular nucleus
  • microparticles
  • p-ERK1/2

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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