HMGB1 and its membrane receptors as therapeutic targets in an intravesical substance P-induced bladder pain syndrome mouse model

J Pharmacol Sci. 2020 Jun;143(2):112-116. doi: 10.1016/j.jphs.2020.03.002. Epub 2020 Mar 12.

Abstract

HMGB1, a nuclear protein, once released to the extracellular space, promotes somatic and visceral pain signals. We thus analyzed the role of HMGB1 in an intravesical substance P-induced bladder pain syndrome (BPS) mouse model. Intravesical administration of substance P caused referred hyperalgesia/allodynia in the lower abdomen and hindpaw without producing severe urothelial damage, which was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin α capable of inactivating HMGB1 and antagonists of RAGE or CXCR4. The HMGB1 inactivation or RAGE blockade also reversed the established bladder pain symptoms. HMGB1 and RAGE are thus considered to serve as therapeutic targets for BPS.

Keywords: Bladder pain syndrome; HMGB1; Substance P.

MeSH terms

  • Animals
  • Antibodies, Neutralizing / therapeutic use*
  • Cystitis, Interstitial / drug therapy
  • Cystitis, Interstitial / etiology*
  • Cystitis, Interstitial / genetics*
  • Disease Models, Animal
  • Female
  • HMGB1 Protein / immunology
  • HMGB1 Protein / physiology*
  • Humans
  • Male
  • Mice, Inbred Strains
  • Molecular Targeted Therapy
  • Receptor for Advanced Glycation End Products / antagonists & inhibitors
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear*
  • Substance P / administration & dosage
  • Substance P / adverse effects*
  • Thrombomodulin / therapeutic use*

Substances

  • Ager protein, mouse
  • Antibodies, Neutralizing
  • CXCR4 protein, mouse
  • HMGB1 Protein
  • HMGB1 protein, mouse
  • Receptor for Advanced Glycation End Products
  • Receptors, CXCR4
  • Receptors, Cytoplasmic and Nuclear
  • Thrombomodulin
  • Substance P