Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice.
This in vivo study assessed the potential of the imidazoline receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.
Laboratory of Neuropharmacology, IUNICS-IdISPa, University of the Balearic Islands (UIB), Palma de Mallorca, Spain Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain.
Benjamin
B
Keller
Laboratory of Neuropharmacology, IUNICS-IdISPa, University of the Balearic Islands (UIB), Palma de Mallorca, Spain Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain jesus.garcia-sevilla@uib.es.
Jesús A
JA
García-Sevilla
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D019329:Idazoxan / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors / Q000187:drug effects* / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008024:Ligands; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D013343:Styrenes / Q000494:pharmacology*; D013997:Time Factors
C121754:2-styryl-2-imidazoline; C105826:BU 224; D001572:Benzofurans; D007093:Imidazoles; D054755:Imidazoline Receptors; D008024:Ligands; D018696:Neuroprotective Agents; D013343:Styrenes; D018698:Glutamic Acid; C043482:moxonidine; D051360:Cyclin-Dependent Kinase 5; C062597:efaroxan; D007608:Kainic Acid; D019329:Idazoxan
I1/I2-imidazoline receptor ligands; excitotoxicity; kainic acid; neuroprotection