Possible neuroprotective effect of brimonidine in a mouse model of ischaemic optic neuropathy.
OBJECTIVE
To investigate the neuroprotective effect of brimonidine following induction of ischaemic optic neuropathy in rodents (rAION).


METHODS
Mice were treated with an intraperitoneal injection of brimonidine 48, 24 or 0 h before rAION induction or eye drops for 5 days after rAION induction. Retinal ganglion cell (RGC) loss and expression of genes involved in the angiogenesis (vascular endothelial growth factor [VEGF], pigment epithelium-derived factor [PEDF], The epidermal growth factor homology domains-2 [Tie-2]), ischaemia (haem oxygense-1 [HO-1], hypoxia-inducible factor 1alpha[HIF-1alpha], endothelial nitric oxide synthase [eNOS]) and oxidative stress (superoxide dismutase-1 [SOD-1], glutathione peroxidase-1 [GPX-1]) response to ischaemic damage were compared with sham or rAION-untreated mice.


RESULTS
No RGC loss was detected in the brimonidine-treated mice. Effect of post-rAION eye drops: day 1--no decrease in retinal mRNA levels of angiogenesis-related genes, increase in ischaemia- and oxidative stress-related genes except HIF-1alpha; day 3--baseline or higher levels of oxidative and ischaemia-related genes except HIF-1alpha, increase in VEGF, decrease in PEDF; day 21--no change in angiogenesis-related genes. Effect of pre-rAION injection: baseline levels of angiogenesis-related genes with all injection schedules; increase in ischaemia-related genes with 48-h and 0-h pretreatment; decrease in HO-1 and eNOS with 24-h pretreatment; increase in oxidative-related genes except GPX-1. In optic nerve tissue, HO-1, HIF-1alpha and SOD-1 decreased on day 1 after topical administration and were still below baseline on day 3.


CONCLUSIONS
The increase in HO-1 associated with rAION is mitigated with brimonidine treatment, especially when administered intraperitoneally. Topical brimonidine apparently reduces VEGF, Tie-2, HIF-1alpha and GPX-1 expression on day 21. These results agree with published data and may have therapeutic implications for patients diagnosed with AION in the acute phase.
Pediatric Division of Ophthalmology, Schneider Children's Medical Center of Israel, Tel Aviv, Israel.
Nitza
N
Goldenberg-Cohen
Shimrit
S
Dadon-Bar-El
Murat
M
Hasanreisoglu
Bat Chen R
BC
Avraham-Lubin
Olga
O
Dratviman-Storobinsky
Yoram
Y
Cohen
Dov
D
Weinberger
D000818:Animals; D000068438:Brimonidine Tartrate; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D005979:Glutathione Peroxidase / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D018917:Optic Neuropathy, Ischemic / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000235:genetics; D011810:Quinoxalines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D042787:Receptor, TIE-2; D012165:Retinal Ganglion Cells / Q000473:pathology; D015861:Retinal Neovascularization / Q000235:genetics; D015843:Serpins / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1; D000099174:Pigment Epithelium-Derived Factor
D000068438:Brimonidine Tartrate; D005136:Eye Proteins; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D052250:Nitric Oxide Synthase Type III; D011810:Quinoxalines; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D015843:Serpins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D042461:Vascular Endothelial Growth Factor A; D000094765:Glutathione Peroxidase GPX1; D000099174:Pigment Epithelium-Derived Factor; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse; C496315:Nos3 protein, mouse; C000606291:Sod1 protein, mouse; C079086:Tek protein, mouse; C000722068:Gpx1 protein, mouse