alpha(2)-Adrenoceptor agonists inhibit vitreal glutamate and aspartate accumulation and preserve retinal function after transient ischemia.
Recent studies have suggested that alpha(2)-adrenergic agonists prevent neuronal cell death in a number of animal models, although the mechanism of alpha(2)-neuroprotection remains unclear. In a retinal ischemia model, the alpha(2)-specific agonist brimonidine (1 mg/kg i.p.) preserves approximately 80% of the electroretinogram (ERG) b-wave. The protective effect of brimonidine is completely blocked by coadministration of the alpha(2)- antagonist rauwolscine. Brimonidine treatment preserves the ERG b-wave if animals are treated 1 or 3 h before ischemia, but has no effect if it is injected during ischemia. The 3-h pretreatment effect is blocked by i.v. injection of rauwolscine 2 h later (1 h before ischemia). A comparison of vitreous humor glutamate levels between untreated and brimonidine-treated eyes shows that 1) after ischemia, glutamate levels rise 2- to 3-fold in the untreated animals, and 2) glutamate levels in the brimonidine-treated animals are comparable to the nonischemic controls. Hence, the mechanism for brimonidine-mediated protection in the retinal ischemia model requires activation of the alpha(2)-adrenergic receptors immediately before and during ischemia. These data suggest that activation of the alpha(2)-adrenergic receptor may reduce ischemic retinal injury by preventing the accumulation of extracellular glutamate and aspartate.
Donello
J E
JE
Department of Biological Sciences, Allergan, Inc., Irvine, California 92612, USA. Donello_john@allergan.com
Padillo
E U
EU
Webster
M L
ML
Wheeler
L A
LA
Gil
D W
DW
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D000068438:Brimonidine Tartrate; D002853:Chromatography, Liquid; D004596:Electroretinography; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D013058:Mass Spectrometry; D011810:Quinoxalines / Q000627:therapeutic use*; D051381:Rats; D011914:Rats, Inbred BN; D012160:Retina / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects / Q000503:physiopathology*; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015016:Yohimbine / Q000494:pharmacology
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011810:Quinoxalines; D015016:Yohimbine; D001224:Aspartic Acid; D018698:Glutamic Acid; D000068438:Brimonidine Tartrate