Chronic treatment with selective I2-imidazoline receptor ligands decreases the content of pro-apoptotic markers in rat brain

J Psychopharmacol. 2013 Feb;27(2):123-34. doi: 10.1177/0269881112450785. Epub 2012 Jun 20.


Selective I(2)-imidazoline receptor ligands induce neuroprotection through various molecular mechanisms including blockade of N-methyl-D-aspartate (NMDA) receptors. To investigate new neuroprotective mechanisms associated with I(2)-imidazoline receptors, the effects of selective (2-styryl-2-imidazoline (LSL 61122), 2-(2-benzofuranyl)-2-imidazoline (2-BFI), 2-(4,5-dihydroimidazol-2-yl) quinoline hydrochloride (BU-224)) and non-selective (idazoxan) I(2)-drugs on canonical apoptotic pathways were assessed in rat brain cortex. The acute treatment with LSL 61122 (10 mg/kg) reduced the content of mitochondrial (pro-apoptotic) Bax (-33%) and cytochrome c (-31%), which was prevented by idazoxan, an I(2)-receptor antagonist. The sustained stimulation of I(2)-imidazoline receptors with selective drugs (10 mg/kg, every 12 h for seven days) was associated with down-regulation of key components of the extrinsic (Fas receptor: -20%; Fas associated protein with death domain (FADD) adaptor: -47-54%) and/or intrinsic (Bax: -20-23%; cytochrome c: -22-28%) apoptotic signalling and/or up-regulation of survival anti-apoptotic factors (p-Ser194 FADD/FADD ratio: +1.6-2.5-fold; and/or Bcl-2/Bax ratio: +1.5-fold), which in the long-term could dampen cell death in the brain. Similar chronic treatments with LSL 60101 (the imidazole analogue of 2-BFI) and idazoxan (a mixed I(2)/α(2)-ligand) did not induce significant alterations of pro- or anti-apoptotic proteins. The disclosed anti-apoptotic mechanisms of selective I(2)-imidazoline drugs may work in concert with other molecular mechanisms of neuroprotection (e.g. blockade of NMDA receptors) that are engaged by I(2)-ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Death / drug effects
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Cytochromes c / metabolism
  • Death Domain Receptor Signaling Adaptor Proteins / metabolism
  • Down-Regulation / drug effects
  • Fas-Associated Death Domain Protein / metabolism
  • Imidazoline Receptors / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Ligands
  • Male
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neuroprotective Agents / pharmacology*
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation / drug effects
  • bcl-2-Associated X Protein / metabolism
  • fas Receptor / metabolism


  • Apoptosis Regulatory Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • Fadd protein, rat
  • Fas-Associated Death Domain Protein
  • Imidazoline Receptors
  • Ligands
  • Neuroprotective Agents
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • fas Receptor
  • imidazoline receptor 2
  • Cytochromes c
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • JNK Mitogen-Activated Protein Kinases