H2S attenuates injury after ischemic stroke by diminishing the assembly of CaMKII with ASK1-MKK3-p38 signaling module

Behav Brain Res. 2020 Apr 20:384:112520. doi: 10.1016/j.bbr.2020.112520. Epub 2020 Jan 30.

Abstract

Cerebral ischemia/reperfusion (I/R) injury is a leading cause of learning and memory dysfunction. Hydrogen sulfide (H2S) has been shown to confer neuroprotection in various neurodegenerative diseases, including cerebral I/R-induced hippocampal CA1 injury. However, the underlying mechanisms have not been completely understood. In the present study, rats were pretreated with SAM/NaHS (SAM, an H2S agonist, and NaHS, an H2S donor) only or SAM/NaHS combined with CaM (an activator of CaMKII) prior to cerebral ischemia. The Morris water maze test demonstrated that SAM/NaHS could alleviate learning and memory impairment induced by cerebral I/R injury. Cresyl violet staining was used to show the survival of hippocampal CA1 pyramidal neurons. SAM/NaHS significantly increased the number of surviving cells, whereas CaM weakened the protection induced by SAM/NaHS. The immunohistochemistry results indicated that the number of Iba1-positive microglia significantly increased after cerebral I/R. Compared with the I/R group, the number of Iba1-positive microglia in the SAM/NaHS groups significantly decreased. Co-Immunoprecipitation and immunoblotting were conducted to demonstrate that SAM/NaHS suppressed the assembly of CaMKII with the ASK1-MKK3-p38 signal module after cerebral I/R, which decreased the phosphorylation of p38. In contrast, CaM significantly inhibited the effects of SAM/NaHS. Taken together, the results suggested that SAM/NaHS could suppress cerebral I/R injury by downregulating p38 phosphorylation via decreasing the assembly of CaMKII with the ASK1-MKK3-p38 signal module.

Keywords: ASK1-MKK3-p38; CaMKII; H(2)S; SAM; ischemia/reperfusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / drug effects*
  • CA1 Region, Hippocampal / metabolism
  • CA1 Region, Hippocampal / pathology
  • Calcium-Binding Proteins / drug effects
  • Calcium-Binding Proteins / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Calmodulin / pharmacology*
  • Down-Regulation
  • Hydrogen Sulfide / metabolism*
  • Ischemic Stroke / metabolism*
  • Ischemic Stroke / physiopathology
  • Learning / drug effects
  • MAP Kinase Kinase 3 / drug effects
  • MAP Kinase Kinase 3 / metabolism
  • MAP Kinase Kinase Kinase 5 / drug effects
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Male
  • Memory / drug effects
  • Memory Disorders / metabolism*
  • Memory Disorders / physiopathology
  • Microfilament Proteins / drug effects
  • Microfilament Proteins / metabolism
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Morris Water Maze Test
  • Phosphorylation
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • Rats
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / physiopathology
  • S-Adenosylmethionine / pharmacology*
  • Sulfides / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Aif1 protein, rat
  • Calcium-Binding Proteins
  • Calmodulin
  • Microfilament Proteins
  • Sulfides
  • S-Adenosylmethionine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase 3
  • Map2k3 protein, rat
  • sodium bisulfide
  • Hydrogen Sulfide