2-Methoxystypandrone ameliorates brain function through preserving BBB integrity and promoting neurogenesis in mice with acute ischemic stroke

Biochem Pharmacol. 2014 Feb 1;87(3):502-14. doi: 10.1016/j.bcp.2013.11.018. Epub 2013 Dec 14.

Abstract

2-Methoxystypandrone (2-MS), a naphthoquinone, has been shown to display an immunomodulatory effect in a cellular model. To explore whether 2-MS could protect mice against cerebral ischemic/reperfusion (I/R)-induced brain injury, we evaluated 2-MS's protective effects on an acute ischemic stroke by inducing a middle cerebral artery occlusion/reperfusion (MCAO) injury in murine model. Treatment of mice that have undergone I/R injury with 2-MS (10-100 μg/kg, i.v.) at 2 h after MCAO enhanced survival rate and ameliorated neurological deficits, brain infarction, neural dysfunction and massive oxidative stress, due to an enormous production of free radicals and breakdown of blood-brain barrier (BBB) by I/R injury; this primarily occurred with extensive infiltration of CD11b-positive inflammatory cells and upexpression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 and p65 nuclear factor-kappa B (NF-κB). All of these pathological changes were diminished by 2-MS; 2-MS also intensively limited cortical infarction and promoted upexpression of neurodevelopmental genes near peri-infarct cortex and endogenous neurogenesis near subgranular zone of hippocampal dentate gyrus and the subventricular zone, most possibly by inactivation of GSK3β which in turn upregulating β-catenin, Bcl-2 adam11 and adamts20. We conclude that 2-MS blocks inflammatory responses by impairing NF-κB signaling to limit the inflammation and oxidative stress for preservation of BBB integrity; 2-MS also concomitantly promotes neurodevelopmental protein expression and endogenous neurogenesis through inactivation of GSK3β to enhance β-catenin signaling for upexpression of neuroprotective genes and proteins.

Keywords: 2-MS; 2-Methoxystypandrone (2MS); 2-methoxystypandrone; B-cell lymphoma 2; BBB; Bcl-2; COX-2; DCX; GSK3; Glycogen synthase kinase 3 (GSK3); I/R; Ischemic stroke; MCAO; NF-κB; SGZ; SVZ; Subgranular zone (SGZ); blood–brain barrier; cyclooxygenase-2; doublecortin; glycogen synthase kinase 3; iNOS; inducible nitric oxide synthase; ischemia reperfusion; middle cerebral artery occlusion/reperfusion; nuclear factor-kappa B; subgranular zone; subventricular zone; β-Catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / drug effects*
  • Brain / drug effects*
  • Brain Ischemia / drug therapy*
  • CD11b Antigen / genetics
  • CD11b Antigen / metabolism
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Doublecortin Protein
  • Gene Expression Regulation / drug effects
  • Immunologic Factors / pharmacology
  • Leukocytes / cytology
  • Leukocytes / metabolism
  • Male
  • Mice
  • Mice, Inbred ICR
  • Molecular Structure
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology*
  • Neurogenesis / drug effects*
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Reperfusion Injury
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Stroke / drug therapy*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism

Substances

  • 2-Methoxystypandrone
  • CD11b Antigen
  • Dcx protein, mouse
  • Doublecortin Protein
  • Immunologic Factors
  • Naphthoquinones
  • Rela protein, mouse
  • Transcription Factor RelA
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2