Affiliation:
1. Laboratori de Neurofarmacologia, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, and Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), Spain
Abstract
Selective I2-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 I2-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) I2-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 I2-receptor antagonist. The sustained stimulation of I2-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 I2/α2-ligand) did not induce significant alterations of pro- or anti-apoptotic proteins. The disclosed anti-apoptotic mechanisms of selective I2-imidazoline drugs may work in concert with other molecular mechanisms of neuroprotection (e.g. blockade of NMDA receptors) that are engaged by I2-ligands.
Subject
Pharmacology (medical),Psychiatry and Mental health,Pharmacology
Cited by
19 articles.
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