Neuroprotective effects of the alpha2-adrenoceptor antagonists, (+)-efaroxan and (+/-)-idazoxan, against quinolinic acid-induced lesions of the rat striatum.
A deficient control of neuronal repair mechanisms by noradrenergic projections originating from the locus coeruleus may be a critical factor in the progression of neurodegenerative diseases. Blockade of presynaptic inhibitory alpha2-adrenergic autoreceptors can disinhibit this system, facilitating noradrenaline release. In order to test the neuroprotective potential of this approach in a model involving excitotoxicity, the effects of treatments with the alpha2-adreneceptor antagonists, (+)-efaroxan (0.63 mg/kg i.p., thrice daily for 7 days) or (+/-)-idazoxan (2.5 mg/kg i.p., thrice daily for 7 days), were evaluated in rats which received a quinolinic acid-induced lesion of the left striatum. Both drug treatments resulted in a reduced ipsiversive circling response to apomorphine and a reduced choline acetyltransferase deficit in the lesioned striatum. The mechanisms underlying this effect are not known for certain, but may include noradrenergic receptor modulation of glial cell function, growth factor synthesis and release, activity of glutamatergic corticostriatal afferents, and/or events initiated by NMDA receptor activation. These results suggest a therapeutic potential of alpha2-adrenoceptor antagonists in neurodegenerative disorders where excitotoxicity has been implicated.
Martel
J
J
Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, Castres Cédex, 81106, France.
Chopin
P
P
Colpaert
F
F
Marien
M
M
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry* / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006816:Huntington Disease / Q000188:drug therapy; D019329:Idazoxan / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D017378:Quinolinic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*
D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D018491:Dopamine Agonists; D007093:Imidazoles; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018341:Receptors, Adrenergic, alpha-2; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid; C062597:efaroxan; D001058:Apomorphine; D019329:Idazoxan